InteractiveFly: GeneBrief

CoRest: Biological Overview | References


Gene name - CoRest

Synonyms -

Cytological map position - 18C8-18C8

Function - Chromatin factor

Keywords - corepressor, regulation of Notch signaling, ovarian follicular cells and wing, component of L(3)mbt repressor complex, component of LSD1-CoREST demethylase complex, regulates DPP signaling, associates with Charlatan

Symbol - CoRest

FlyBase ID: FBgn0261573

Genetic map position - chrX:19416060-19424937

Classification - SANT SWI3, ADA2, N-CoR and TFIIIB'' DNA-binding domains

Cellular location - nuclear



NCBI links: Precomputed BLAST | EntrezGene
BIOLOGICAL OVERVIEW

The Notch signaling pathway plays important roles in a variety of developmental events. The context-dependent activities of positive and negative modulators dramatically increase the diversity of cellular responses to Notch signaling. In a screen for mutations affecting the Drosophila follicular epithelium, a mutation was isolated in CoREST that disrupts the Notch-dependent mitotic-to-endocycle switch of follicle cells at stage 6 of oogenesis. Drosophila CoREST positively regulates Notch signaling, acting downstream of the proteolytic cleavage of Notch but upstream of Hindsight activity; the Hindsight gene is a Notch target that coordinates responses in the follicle cells. CoREST genetically interacts with components of the Notch repressor complex, Hairless, C-terminal Binding Protein and Groucho. In addition, it was demonstrated that levels of H3K27me3 and H4K16 acetylation are dramatically increased in CoREST mutant follicle cells. The data indicate that CoREST acts as a positive modulator of the Notch pathway in the follicular epithelium as well as in wing tissue, and suggests a previously unidentified role for CoREST in the regulation of Notch signaling. Given its high degree of conservation among species, CoREST probably also functions as a regulator of Notch-dependent cellular events in other organisms (Domanitskaya, 2012).

The highly conserved Notch signaling pathway plays a crucial role in a broad array of developmental events, including the maintenance of stem cells, cell fate specification, control of proliferation and apoptosis. Misregulation of the Notch pathway is associated with a number of diseases, including different types of cancer. The binding of the transmembrane ligands DSL (Delta, Serrate, LAG-2) to the extracellular domain of Notch, exposed on a neighboring cell, activates the signaling cascade by triggering a sequence of proteolytic cleavages of Notch protein. Extracellular cleavage (S2) leads to the formation of an intermediate membrane-bound C-terminal fragment of Notch, called NEXT. This event is followed by an intramembranous cleavage (S3) by the γ-secretase complex. The intracellular domain of Notch (NICD) then translocates to the nucleus and binds to a transcription factor of the CSL family [CBF-1, Su(H), LAG-1], converting it from a transcriptional repressor to an activator. In the canonical Notch pathway, Su(H) directly activates Notch target genes in response to signaling. Despite the relative simplicity of the Notch transduction pathway, the presence of a large number of proteins that positively or negatively influence Notch signaling dramatically increases the complexity of the Notch pathway and its cellular responses. For instance, extracellular modulators, such as Fringe, alter ligand-specific Notch activation, whereas cytoplasmic modulators, such as Numb, restrict signal transduction. Nuclear modulators, for instance Mastermind, influence the transcriptional activity of the NICD-containing complex. In addition, there is increasing evidence of the importance of the epigenetic regulation of Notch targets, which can cause differential cellular responses upon Notch activation (Domanitskaya, 2012).

Drosophila serves as an excellent model system to dissect the regulation of the Notch pathway. The Drosophila genome contains only a single Notch protein and two ligands [Delta (Dl) and Serrate (Ser)]. The Notch pathway is involved in several aspects of Drosophila development. The role of Notch in lateral inhibition during neurogenesis has been extensively studied; it restricts neural cell fates in the embryo, and leads to restriction of sensory-organ formation and induction of boundary formation in the wing discs. Notch activity is also required for many aspects of oogenesis, such as the establishment of egg chamber polarity, polar cell formation, control of follicle cell (FC) proliferation, differentiation, cell fate specification and morphogenesis. The Drosophila FCs are somatically derived epithelial cells that form a monolayer covering the germline cells during oogenesis. FCs divide mitotically from stage 2 to stage 6 of oogenesis, followed by the switch from the mitotic cycle to the endocycle (the M/E transition). Endocycles take place from stage 7 to stage 10A of oogenesis and include three rounds of DNA duplication without subsequent cell division. The M/E switch is triggered upon Notch pathway activation. Dl produced in the germline binds to its receptor Notch, expressed in the FCs, and induces activation of the canonical Notch signaling pathway. Removal of Dl from germline cells, or of Notch from FCs, maintains follicle cells in the mitotic cycle throughout oogenesis. NICD complexed with Su(H) activates transcription of downstream target genes required for the M/E switch, such as Hindsight (Hnt). Hnt then mediates the Notch-dependent downregulation of Cut, String (Stg) and Hedgehog (Hh) signaling in the FCs, thus promoting the M/E switch (Domanitskaya, 2012).

This study describes the identification of the transcriptional cofactor Corepressor for element-1-silencing transcription factor (CoREST) as a positive modulator of Notch signaling in the FCs and during wing development. CoREST is required for the promotion of the M/E switch during oogenesis. CoREST acts downstream of NICD release but upstream of Hnt activity, and it is a previously unidentified modulator of the Notch pathway. The genetic interactions between CoREST and Hairless (H), CtBP and Groucho (Gro), members of the Notch repressor complex, suggest that CoREST might influence the activity of either Notch transcriptional repressor or activator complexes. In addition, CoREST specifically affects tri-methylation of lysine 27 of histone 3 (H3K27) and acetylation of H4K16 in FCs, because these chromatin modifications show elevated levels in the CoREST mutant cells. These findings point to a possible role of CoREST in regulation of the activity of the Notch repressor-activator complexes and/or epigenetic regulation of the components of the repressor-activator complexes or of factors involved in the transduction of the signaling or directly of target genes of the Notch signaling pathway (Domanitskaya, 2012).

Initially, CoREST was identified in humans as a corepressor with REST (RE1 silencing transcription factor) in mediating repression of the proneuronal genes, and thus as an important factor in the establishment of non-neural cell specificity (Andres, 1999; Lunyak, 2002). Subsequently, CoREST was identified in a variety of vertebrate and invertebrate species, and was shown to play a functionally conserved role in neurogenesis (Tontsch, 2001; de la Calle-Mustienes, 2002; Jarriault, 2002; Dallman, 2004). Recent studies show that CoREST regulates a very broad range of genes by both REST-dependent and REST-independent means, including genes encoding members of key neural developmental signaling pathways, such as BMP, SHH, Notch, RA, FGF, EGF and WNT (Abrajano, 2009a; Abrajano, 2010; Qureshi, 2010). Analysis of CoREST downstream target genes and their developmental expression profiles suggested that the liberation of CoREST from gene promoters is associated with both gene repression and activation depending on the cell context (Abrajano, 2009a; Abrajano, 2009b; Abrajano, 2010). In the work reported in this study, a lethal allele of Drosophila CoREST was isolated, and the contribution of CoREST to the development of FCs, a process that involves cell proliferation and differentiation, was analyzed. This study has implicated CoRESTin the regulation of Notch signaling, and acts as a positive modulator of the Notch pathway in Drosophila FCs (Domanitskaya, 2012).

This study has identified a role for CoREST in the Notch-mediated regulation of the M/E switch during stage 6 of oogenesis. Loss of CoREST activity in FCs primarily disrupts the Notch signaling pathway. We further demonstrated that CoREST regulates the Notch pathway downstream of NICD release and upstream of Hnt. The misexpression of Hnt in the CoREST mutant clones rescues the failure in the M/E switch. Furthermore, the role of CoREST in Notch pathway regulation is not restricted to FCs: CoREST also interacts with Notch during wing development. Interestingly, CoREST was identified as a negative modulator of Notch signaling in Caenorhabditis elegans in a genetic screen for suppressors of the developmental defects in sel-12 presenilin mutants (Eimer, 2002; Jarriault, 2002; Lakowski, 2006). Presenilin is a component of the γ-secretase complex that performs the S3 cleavage of Notch. Mutations in spr-1, the C. elegans homolog of CoREST, suppress the developmental defects observed in sel-12 animals by derepressing the transcription of the other functionally redundant presenilin gene, hop-1 (Jarriault, 2002; Lakowski, 2006). Therefore, CoREST acts as a negative regulator of the γ-secretase complex in C. elegans, and hence proteolytic cleavage of Notch and release of NICD. By contrast, Drosophila CoREST does not affect the processing of the Notch receptor in the follicle cells, and instead acts as a positive modulator of the Notch pathway functioning downstream of NICD release (Domanitskaya, 2012).

CoREST plays transcriptional and epigenetic regulatory roles: it can promote gene activation in addition to repression, as well as being able to modify the epigenetic status of target gene loci distinct from its effects on transcription (Qureshi, 2010). Several possible scenarios of how CoREST could be involved in the regulation of Notch signaling are discussed, based on the previous knowledge about CoREST and considering the current data (Domanitskaya, 2012).

hnt, the downstream target gene of Notch signaling in FCs, fails to be properly upregulated upon Notch activation in the CoREST mutant cells. CoREST might therefore act as a transcriptional repressor for an unknown factor, which is in turn involved in the transcriptional repression of hnt. Alternatively, CoREST could be directly involved in the transcriptional regulation of hnt and act as an activator. hnt was shown to be a putative direct target of Notch signaling in DmD8 cells (Krejci, 2009) from the analysis of genes for which mRNA levels increase within 30 minutes of Notch activation, and which contain regions occupied by Su(H). If hnt is a direct target of Notch in FCs, its transcription would be regulated by the balance between Notch repressor and activator complexes, and CoREST might be involved in the regulation of stability or activity of either of these. Interestingly, CoREST was shown to interact with CtBP1 in mammals (Kuppuswamy, 2008), and to bind to the SIRT1-LSD1-CtBP1 complex, which is required for the repression of certain Notch target genes (Mulligan, 2011). Thus, Drosophila CoREST might similarly directly bind to the repressor complex containing CtBP and modify its activity or destabilize it. However, CoREST could be involved in the transcriptional regulation of the components of Notch repressor or activator complexes. In this scenario, in CoREST mutant FCs, upregulation of negative regulator(s) would lead to greater activity of negative than positive regulators, resulting in disruption of Notch signaling. Both suggested models of the direct and indirect transcriptional role of CoREST are consistent with the current results, given that the CoREST mutant phenotype could be suppressed by removal of one copy of H, CtBP or Gro, components of the Notch repressor complex (Domanitskaya, 2012).

More recently, epigenetic mechanisms have emerged as an important interface regulating context-dependent and stage-specific gene regulation. Mammalian CoREST acts as a scaffold for recruitment of transcriptional regulators such as REST, and epigenetic factors such as the enzymes HDAC1, HDAC2 and LSD1 (Lakowski, 2006; Qureshi, 2010). In Drosophila, using two-hybrid interaction, CoREST was also shown to interact with Su(VAR)3-3 (Drosophila homolog of LSD1) and Rpd3 (HDAC1) (Dallman, 2004). This study has shown that the levels of H3K27me3 and H4K16 acetylation are significantly and specifically increased in the CoREST mutant FCs. Recently, the H3K27me3 demethylase UTX was shown to act as a suppressor of Notch- and Rb-dependent tumors in Drosophila eyes (Herz, 2010), and in addition to increased level of H3K27me3 staining, an excessive activation of Notch was detected in Utx mutant eye discs. The observation of increased levels of H3K27me3 coupled to cell overproliferation and modified Notch signaling in both of these cases [(Herz, 2010) and this study] suggests that the increased H3K27me3 results in epigenetic regulation of genes involved in Notch signaling and/or of Notch target genes. However, in the eye tumor system, this increase in H3K27me3 promotes Notch signaling, whereas in the follicle cells, it reduces Notch signaling. This indicates a strong context-dependent effect on Notch signaling by certain chromatin modifications. Thus, these chromatin modifications might be involved in cell-context-dependent Notch target gene silencing and/or activation (Schwanbeck, 2011). Interestingly, many Notch-regulated genes are highly enriched in a characteristic chromatin modification pattern, termed a bivalent domain, consisting of regions of H3K4me3, a marker for actively expressed genes, and H3K27me3, a marker for stably repressed genes; and Notch signaling could be involved in resolving these domains, leading to gene expression (Schwanbeck, 2011). Therefore, the increased level of H3K27me3 in CoREST mutant FCs might lead to a repression of certain Notch target genes, for instance hnt (Domanitskaya, 2012).

To further understand the function of the Drosophila CoREST in Notch pathway regulation, identification of other CoREST essential and specific binding partners would be useful. One previously identified partner for CoREST is Chn (Tsuda, 2006). Given that wild-type expression of Hnt and Cut was observed in chn mutant cells, this factor does not appear to partner CoREST in regulation of Notch signaling in FCs. Using yeast two-hybrid analyses and an embryonic cDNA fusion protein library, it was shown that all three splice variants of Drosophila CoREST interact with the unique C-terminus of Tramtrack88 (Ttk88), a known repressor without homology to REST (Dallman, 2004). In addition, a Ttk69 splice variant can form a complex with CoREST and Ttk88 (Dallman, 2004). However, Ttk88 was not detected in the ovary by immunofluorescence or western blot analysis, and disruption of Ttk88 does not have any impact on oogenesis. Conversely, Ttk69 is steadily expressed in FCs before stage 10 and it is required for the M/E transition. However, in contrast to CoREST, which acts upstream of Hnt, Hnt expression is not affected in ttk1e11 mutant FCs, indicating a role of Ttk69 downstream of Hnt in the control of the M/E switch. Additionally, Ttk69 is not required for cell differentiation, as expression of FasIII, a cell fate marker for immature follicle cells, is normal in ttk1e11 mutant FCs. From these important phenotypic differences between Ttk69, Ttk88 and CoREST, it appears that CoREST plays a Ttk-independent role in Notch pathway regulation in the FCs. Future work to identify transcription regulators that act as binding partners of CoREST will help in determining the precise biochemical role of CoREST in modulating Notch signaling (Domanitskaya, 2012).

These results demonstrate an unexpected role for CoREST in positively regulating Notch signaling. The effect of the loss of CoREST is particularly strong in the PFCs and relatively mild in the lateral and anterior follicle cells. This implies that CoREST is crucially required in cells that are more sensitive to loss of Notch signaling. The difference between the PFCs and the other follicle cells is established at approximately stages 6-7 of oogenesis by EGF receptor activation in response to Gurken produced by the oocyte. EGF signaling, therefore, is active around the same time as the Notch pathway and hence it is probable that downstream effector(s) of EGFR signaling result in the increased sensitivity of PFCs to the loss of CoREST. In the model of CoREST negatively affecting a repressor of Notch signaling, EGFR signaling would be expected to act positively to enhance expression and/or activity of a Notch repressor. Thus, loss of CoREST from the PFCs would occur in a cell type where repressor activity is already augmented, which would explain the observation of differential loss of Notch signaling in the PFCs (Domanitskaya, 2012).

In summary this study has shown that CoREST, a component of transcriptional repressor complexes, acts positively in Notch signaling in the ovarian follicle cells of Drosophila. The results also show that different cell types are differentially sensitive to loss of this repressor. Future identification of partners and targets of CoREST in the follicle cells should further elucidate how activity of EGFR and other signaling pathways are integrated in this process (Domanitskaya, 2012).

LINT, a Novel dL(3)mbt-Containing Complex, Represses Malignant Brain Tumour Signature Genes

Mutations in the l(3)mbt tumour suppressor result in overproliferation of Drosophila larval brains. Recently, the derepression of different gene classes in l(3)mbt mutants was shown to be causal for transformation (Richter, 2011). However, the molecular mechanisms of dL(3)mbt-mediated gene repression are not understood. This study identified LINT, the major dL(3)mbt complex of Drosophila. LINT has three core subunits -- dL(3)mbt, dCoREST, and l(3)mbt interacting protein 1 (dLint-1) -- and is expressed in cell lines, embryos, and larval brain. Using genome-wide ChIP-Seq analysis, it was shown that dLint-1 binds close to the TSS of tumour-relevant target genes. Depletion of the LINT core subunits results in derepression of these genes. By contrast, histone deacetylase, histone methylase, and histone demethylase activities are not required to maintain repression. These results support a direct role of LINT in the repression of brain tumour-relevant target genes by restricting promoter access (Meier, 2012).

LINT subunit composition differs from the human L3MBTL1 complex which contains pRb, HP1γ, H1b and core histones. dLint-1 has no apparent homolog in mammals. The mammalian homologs of dCoREST exist in complexes containing LSD1 and HDAC1/2. dLsd1 and dRpd3 are not stably associated with LINT. Nevertheless, the LINT subunit dLint-1 associates with dCoREST, dLsd1 and dRpd3 arguing for the existence of complexes in Drosophila that are related to mammalian CoREST/LSD1 complexes. Two observations are consistent with the view that these complexes might associate with chromatin and occupy sites that are not bound by LINT. First, dLint-1 is associated with approximately 50 bands on polytene chromosomes that show no dL(3)mbt binding. Second, ChIP-Seq analysis has revealed 2,902 dL(3)mbt binding sites but more than 8,000 dLint-1 binding sites. The functional relationship between these different dLint-1-containing complexes is unclear (Meier, 2012).

Comparison of genomewide binding profiles of dL(3)mbt in larval brain and dLint-1 in S2 and Kc cells strongly argues that LINT subunits bind to a large set of common binding sites. In particular, MBTS germline-related genes are bound and often repressed by the three LINT subunits. The finding that LINT exists in larval brain strongly implies that it is the LINT complex that is inactivated in l(3)mbtts mutants. In addition to malignant brain tumour signature (MBTS) genes, genes targeted by the Salvador-Warts-Hippo (SWH) pathway have recently been shown to be deregulated in l(3)mbtts brains (Richter 2011). Although binding of dLint-1 to about half of the SWH targets was detected, changes in SWH target gene expression following depletion of dL(3)mbt or dLint-1 has not been detected in Kc cells. It is possible that protein depletion was not sufficient to derepress these genes under the conditions used. Also, SWH target genes might be regulated differently in larval brain compared to cell lines (Meier, 2012).

The results suggest that maintenance of MBTS germline gene repression by LINT is largely independent of repressive histone modifying activities. Depletion of the dLint-1-associated histone demethylase dLsd1 and dRpd3 enzymes does not lead to derepression of LINT targets. An increase of the active H3K4me2 mark was detected at derepressed LINT target genes but this is most likely a result of active transcription rather than a direct consequence of the loss of LINT associated chromatin modifying activities. In agreement with this view, depletion of dLsd1 does not result in changes of H3K4me2 levels at LINT target genes. Microarray analysis also did not detect significant changes in the expression of genes recently shown to be repressed by dLsd1 in S2 cells and developing flies. This suggests that LINT and dLsd1 target different sets of genes (Meier, 2012).

Chromatin association and the repressive potential of human L3MBTL1 is enhanced by PR-SET7 and H4K20 monomethylation (Trojer, 2007; Kalakonda, 2008). Depletion of dPR-Set7, the sole Drosophila enzyme responsible for H4K20 monomethylation, did not result in derepression of LINT targets. Also no significant levels of H4K20me1 was detected at promoters of LINT target genes. This strongly suggests that even though dL(3)mbt can bind H4K20me1 in vitro this interaction does not play an important role in LINT complex targeting and repression (Meier, 2012).

dL(3)mbt does also bind to H4K20me2 in vitro. Indeed, H4K20me2 is present at LINT-regulated genes. However, H4K20me2 levels are are not elevated at LINT target gene promoters compared to control regions. This finding was not surprising given that 85%-90% of all histone H4 molecules are dimethylated at K20 and, therefore, H4K20me2 levels might be expected to be uniformely high along the chromosome. This makes it unlikely that an interaction between the MBT domains and H4K20me2 specifically directs the LINT complex to its target genes. However, it remains possible that after recruitment of LINT by other means, an interaction between dL(3)mbt and H4K20me2 contributes to transcriptional repression (Meier, 2012).

Depletion of other enzymes setting repressive histone marks such as H3K9me3 and H3K27me3 has likewise no effect on LINT-mediated repression. Although it was not possible to test all histone modifying enzymes for their roles in LINT target gene repression, the results argue for a largely histone modification independent mode of repression. LINT subunits bind predominantly near TSSs suggesting that LINT might inhibit transcription by restricting the access of RNA polymerase II or transcription factors to promoters. In support of this model, recruitment of LINT subunits to the promoter of a reporter gene is sufficient for repression even under conditions where the levels of repressive histone modification enzymes are reduced. Two modes of promoter access restriction by LINT can be envisioned that are not mutually exclusive. First, LINT might bind to the promoter segments required for RNA polymerase II recruitment. Second, as has been suggested for human L3MBTL1, LINT might locally compact nucleosomes. Two of the findings are inconsistent with the latter hypothesis. Nucleosome compaction by L3MBTL1 is dependent on the presence of the H4K20me1 modification. However, as discussed above, ablation of this modification does not result in derepression of LINT target genes. In addition, as a consequence of nucleosome compaction at LINT bound promoters one might expect a local increase in nucleosome density. However, histone H3 ChIP experiments have shown that the promoters of LINT target genes are generally depleted of nucleosomes. While these findings do not rule out a local nucleosome compaction that is - once established - independent of H4K20 monomethylation and undetectable by H3 ChIP, we favour the simpler hypothesis that LINT association with promoter sequences prevents transcription factors and RNA polymerase II from promoter binding (Meier, 2012).

The dL(3)mbt and dCoREST subunits of LINT are well conserved. Similar to the derepression of germline-related genes in l(3)mbtts tumours, misexpression of testis-specific genes (so-called cancer testis antigens) have been described in many human tumours. Based on this study, it is conceivable that L3MBTL1 or CoREST play a role in the repression of cancer testis antigens (Meier, 2012).

Drosophila LSD1-CoREST demethylase complex regulates DPP/TGFβ signaling during wing development

The choice and timing of specific developmental pathways in organogenesis are determined by tissue-specific temporal and spatial cues that are acted upon to impart unique cellular and compartmental identities. A consequence of cellular signaling is the rapid transcriptional reprogramming of a wide variety of target genes. To overcome intrinsic epigenetic chromatin barriers to transcription modulation, histone modifying and remodeling complexes are employed. The deposition or erasure of specific covalent histone modifications, including acetylation, methylation, and ubiquitination are essential features of gene activation and repression. This study has found that the activity of a specific class of histone demethylation enzymes is required for the specification of vein cell fates during Drosophila wing development. Genetic tests revealed that the Drosophila LSD1-CoREST complex is required for proper cell specification through regulation of the DPP/TGFβ pathway. An important finding from this analysis is that LSD1-CoREST functions through control of rhomboid expression in an EGFR-independent pathway (Curtis, 2013).

The Su(var)3-3 gene (CG17149) encodes the Drosophila LSD1 homolog. Mutations in Su(var)3-3 result in aberrant histone methylation and heterochromatin formation, with increased global levels of H3K4me2 and impaired heterochromatic gene silencing. A physical association between LSD1 and CoREST has been described in Drosophila (Dallman, 12 2004), revealing that the critical relationship between these proteins is conserved. LSD1 has an important role in organogenesis and germ line maintenance, such as during mouse anterior pituitary development (Wang, 2007) and Drosophila ovary and wing development. LSD1 also regulates neural stem cell proliferation by modulating signaling via the orphan nuclear receptor TLX (Sun, 2010)¸ and LSD1 appears to have distinct functions in mammalian neuronal morphogenesis (Fuentes, 2012; Zibetti, 2010) as well as stem cell self-renewal and differentiation (Adamo,2011). In humans, loss of LSD1 has been strongly correlated with several types of cancer and high-risk tumors, including prostate cancer, breast cancer and neuroblastomas). In contrast, overexpression of LSD1 has also been linked to some cancers. As a consequence of the emerging links between histone demethylase functions and disease, an understanding how LSD1 contributes to specific cell-cycle regulation and developmental processes is crucial (Curtis, 2013).

The Drosophila wing provides an outstanding in vivo model system to identify factors that regulate cell-fate determination as alterations in cell-fate can often be observed at the single cell level. Multiple conserved signaling pathways contribute to wing patterning and development and are regulated, in part, by the coordinated activities of chromatin remodeling complexes and epigenetic modifying enzymes. Previously work has identified histone lysine demethylase enzymes as coregulators of Brm complex remodeling activities in a genetic screen for factors that influenced a wing patterning phenotype associated with a conditional loss-of-function mutation in the snr1 gene that encodes a core regulatory subunit of the Brm complex. Genetic interaction tests indicated that lsd1 (Su[var]3-3) most likely interacted with the PBAP subtype of the Brm complex (Curtis, 2011). This report further addresses how LSD1 contributes to the cell-type and developmental time-point specific regulation of conserved signaling pathways by understanding its contribution to wing patterning and development (Curtis, 2013).

Recently, it was suggested that LSD1 regulates notch signaling during Drosophila wing development (Mulligan, 2011). This study presents evidence from genetic interaction analyses and tissue or cell-type specific targeted depletion experiments that suggest LSD1 and CoREST/CG42687 (synonymous with CG33525) may also regulate the DPP/TGFβ signaling pathway in a noncanonical manner, by regulating expression of rhomboid, a key player in canonical EGFR signal transduction. This is the first demonstration of LSD1-CoREST regulated DPP/TGFβ signaling and the results further define important roles of the LSD1-CoREST complex in tissue patterning (Curtis, 2013).

The appropriate elaboration of wing vein and intervein cell fates depends on the interplay of factors that promote and those that repress or block vein cell differentiation. In this study, we provide genetic evidence suggesting an important role for lsd1 and CoRest in repressing vein-promoting genes in intervein cells. Ectopic vein development can result from either the loss of a factor required for repressing vein cell differentiation or the gain of a factor that promotes vein cell fate in intervein cells. The experimental results suggest that lsd1 and CoRest utilize the first mechanism, since the aos hypomorphic mutation (aosw11), a factor known to repress vein fate, is enhanced by CoRestEY14216 and lsd1ΔN and targeted depletion by shRNAi of lsd1 and CoRest throughout the entire developing wing imaginal disc resulted in ectopic veins rather than loss of vein phenotypes. It was reasoned that if the LSD1-CoREST complex normally functions as a positive factor to promote vein development as proposed by the second mechanism, then mutations in lsd1 and CoRest or shRNAi depletion in the wing imaginal disc should produce a loss of vein phenotype. Based on the evidence presented in this manuscript, and on the recent finding that LSD1 is important for the regulation of NOTCH signaling in the wing (Di Stefano, 2011), it is proposed that the requirements of LSD1-CoREST are temporal and cell-type specific, and possibly dependent on the physical associations between LSD1 and several multiprotein complexes (Curtis, 2013).

An elaborate signaling network regulates wing patterning, where considerable cross-talk and functional redundancy connects five developmental pathways. For example, during pupal development, the main role of EGFR and DPP activation is to coordinately promote and maintain differentiation into vein cells while NOTCH activation establishes the provein-intervein boundary. However, DPP and NOTCH pathways are codependent, since expression of the NOTCH ligand, DELTA (DL) and its downstream target, ENHANCER OF SPLIT, (E(spl)mβ), require DPP signaling. LSD1 has been shown to interact directly with the histone deacetylase SIRT1 to repress NOTCH targets, suggesting important epigenetic functions for these co-repressors in metazoan development. However, recently it was shown that CoREST could function as a positive regulator of NOTCH in Drosophila follicle cells and wings (Domanitskaya, 2012). Therefore, there is growing precedent for the LSD1-CoREST complex to have both positive and negative roles in regulating gene expression depending on developmental context (Curtis, 2013).

LSD1 and CoREST depletion in the developing wing causes bifurcated or duplicated crossveins, a phenotype previously observed with Hairless (H) loss of function mutations. Because H both antagonizes NOTCH and promotes EGFR signaling, it is difficult to decipher the individual pathway regulated by LSD1-CoREST. Furthermore, the broadened vein delta phenotype observed at the wing margin in wing-specific LSD1-CoREST depleted and lsd1ΔN null flies (Di Stefano, 2011) is similar to Notch and DPP receptor (tkv) loss of function phenotypes (Curtis, 2013).

It is proposed that during the initial stages of wing vein development and differentiation, LSD1 negatively regulates NOTCH signaling. This is based on the observation that loss of lsd1 function suppresses the notched wing phenotype associated with mutations in suppressor of hairless (Su[HT4]) (Mulligan, 2011). However, later in development during vein refinement and maintenance, LSD1 appears to undergo a regulatory switch to positively regulate NOTCH signaling, since lsd1ΔN suppresses the short vein phenotype associated with the gain-of-function NAx-16 mutation. Additionally, the increased expression of downstream E(spl) targets in NAx-16 mutants is reversed by lsd1ΔN (Di Stefano, 2011). It was also recently shown that a transheterozygous mutant allele of CoRest (CoRestGF60) could enhance the wing phenotypes of flies carrying alleles of Dl and N (Domanitskaya, 2012), suggesting positive functions in regulating NOTCH signaling. Concurrently, LSD1 and CoREST repress vein cell differentiation by regulating components of the DPP signaling pathway at multiple points. For example, lsd1ΔN and CoRestEY14216 genetically interact with both dpp and genes encoding its receptors (e.g., dpp, tkv, sax), consistent with upstream functions. Strong genetic interactions were observed with downstream DPP signaling components (e.g., mad, med, ara, caup, shn), which suggests that the LSD1-CoREST complex has important regulatory functions in controlling the expression of DPP pathway targets. This conclusion is further supported by ectopic expression of the DPP-specific downstream signaling component, p-MAD, was observed in LSD1-CoREST-depleted animals. Activated DPP signaling is confined to proveins largely by the overexpression of TKV, a member of the TGFβ receptor family, in intervein boundary cells. TKV binds and sequesters the DPP morphogen. When TKV is downregulated, DPP spreads into regions of the wing destined to become intervein cells, resulting in ectopic veins. It is predicted that TKV is the most likely target of LSD1-CoREST complex regulation, since genetic interactions were observed between lsd1ΔN and CoRestEY14216 and almost all loss of function mutations in DPP signaling components, and tissue-specific LSD1-CoREST depletion lead to the development of ectopic veins, similar to phenotypes observed with loss of function alleles of tkv. Because activation of NOTCH and repression of DPP signaling are both required to repress vein promoting genes in differentiating intervein cells, LSD1 appears to have cell-type and context-specific activities to differentially regulate these pathways (Curtis, 2013).

Coimmunoprecipitation experiments suggested a complex forms between the HDAC1/2 class protein RPD3, LSD1, CoREST, and two TTK splice variants TTK88 or TTK69 (Dallman, 2004). Complexes containing CoREST/TTK69 or CoREST/TTK88 independently localize on polytene salivary glands, suggesting differential gene targeting (Dallman, 2004). TTK and REST are likely functional homologs. Orthologs of tramtrack only exist in invertebrates, whereas REST orthologs are vertebrate-specific (Dallman, 2004). TTK69 is a transcription factor that can recognize and bind to a specific DNA RE-1 consensus sequence (CCAGGACG), resulting in gene transcription (Dallman, 2004). Unpublished observations suggest that TTK69, but not TTK88, function to negatively regulate vein cell development, since an incomplete vein phenotype is observed when TTK69 is overexpressed, whereas overexpression of TTK88 results in the development of ectopic veins. Therefore, it is predicted that LSD1-CoREST-TTK69 form a complex in developing wing tissue to negatively regulate DPP signaling in intervein cells. Furthermore, in mammals, the Brg1 complex chromatin remodeling capacity and recruitment specificity depends on formation of a LSD1-CoREST-REST-BRG1 complex (Ooi 2006). Because LSD1 can physically associate with the Brm chromatin remodeling complex in Drosophila (Curtis, 2011), it is predicted that the Brm complex-LSD1-CoREST-TTK69 super-complex regulates genes essential for wing patterning, possibly through co-localization or recruitment to RE-1 consensus binding sites. Intriguingly, RE-1 consensus sites are present in both the rho and tkv gene loci, making these exciting targets for future investigation (Curtis, 2013).

An NRSF/REST-like repressor downstream of Ebi/SMRTER/Su(H) regulates eye development in Drosophila

The corepressor complex that includes Ebi and SMRTER is a target of epidermal growth factor (EGF) and Notch signaling pathways and regulates Delta (Dl)-mediated induction of support cells adjacent to photoreceptor neurons of the Drosophila eye. A mechanism is described by which the Ebi/SMRTER corepressor complex maintains Dl expression. charlatan (chn) is repressed by Ebi/SMRTER corepressor complex by competing with the activation complex that includes the Notch intracellular domain (NICD). Chn represses Dl expression and is critical for the initiation of eye development. Thus, under EGF signaling, double negative regulation mediated by the Ebi/SMRTER corepressor complex and an NRSF/REST-like factor, Chn, maintains inductive activity in developing photoreceptor cells by promoting Dl expression (Tsuda, 2006).

The corepressor complex that includes Ebi, SMRTER and Su(H) is required for expression of Dl in Drosophila photoreceptor cells. To identify genetic loci that are transcriptionally repressed by the Ebi corepressor, a screen was set up using an ectopic gene expression system (Gene Search System). Insertion of a Gene Search (GS) vector, a modified P-element carrying the Gal4 upstream activating sequence (UASG) near its 3' end, causes overexpression of a nearby gene under the control of the Gal4-UASG system. GS insertions into the chn locus were identified, whose overexpression phenotype in the eye using an eye-specific Gal4 driver (GMR-Gal4) was modified by reducing ebi activity. Thus the regulation of chn by Ebi-dependent transcriptional repression was studied (Tsuda, 2006).

In third instar larval-stage eye discs, the chn transcript is highly expressed in the morphogenetic furrow (MF), where photoreceptor differentiation initiates, but is downregulated in cells in the later stage photoreceptor development. In ebi mutant eye discs, however, chn expression becomes detectable in differentiating photoreceptor cells, and its expression in the MF is increased, suggesting that Su(H) in association with Ebi and SMRTER represses chn transcription in the eye disc (Tsuda, 2006).

To reveal the role of Su(H) as an activator, chn expression was examined when the level of Su(H) expression was reduced. Removing one copy of Su(H) suppresses the loss-of-Dl expression phenotype in ebi mutants. It was found that reducing one copy of Su(H) suppresses ectopic chn expression in ebi mutants, suggesting that ectopic expression of chn in ebi mutants is Su(H)-dependent. RT-PCR analysis of chn expression in ebi- eye discs differing in the dosage of Su(H) gene also supported these results. Strong reduction of Su(H) expression alone reduced expression of chn in the MF; this expression became weaker and was slightly broader. The phenotype of ebi, Su(H) double mutants is almost the same as Su(H) single mutants , suggesting that Su(H) acts as an activator in the absence of Ebi. This might be due to dual functions of Su(H) as an activator or repressor. Hence, reducing the amount of Ebi in the corepressor complex involving Su(H) might convert Su(H) to an activator by permitting the replacement of the corepressor complex with NICD (Tsuda, 2006).

To reveal the molecular nature of transcriptional regulation of chn by Su(H), Su(H) target sites were sought in the genomic region of chn. Since Su(H) binds slightly degenerate sequences, it was not easy to identify the functional Su(H) binding region from a simple genomic search. An alternative approach was taken to map the chn genomic region, which is regulated by Su(H) in the normal chromosomal context. Ebi-mediated repression involves SMRTER, a corepressor that recruits histone deacetylases and induces the formation of inactive chromatin, which spreads from the site where Su(H) recruits the corepressor complex. Promoters near the Su(H)-binding site are thus expected to be downregulated in an Ebi-dependent manner. Four insertion lines of the GS vector were identified in the chn promoter region. All these GS lines caused ectopic expression of chn with consequent abnormal eye morphology when they were crossed with GMR-Gal4. If the effect of the Ebi/SMRTER corepressor complex reaches the UASG in those insertions, reduction of Ebi activity will derepress UASG and further enhance activation by GMR-Gal4. One copy of a dominant-negative construct of ebi (GMR-ebiDN) caused only a mild defect in eye morphology and weak, if any, ectopic expression of chn. GMR-ebiDN strongly enhanced the overexpression phenotype of chnGS17605 and chnGS11450, which contained GS vector insertions (-474 and -734, respectively) upstream of the transcriptional start site. However, GMR-ebiDN failed to enhance the overexpression phenotype of other GS lines (chnGS2112 and chnGS17892) that were inserted downstream (+773 and +1040, respectively) of the first exon. From these results, it is concluded that Ebi-dependent transcriptional repression is targeted to the proximity of the transcriptional initiation site of the chn promoter (Tsuda, 2006).

Chn is a 1108-amino-acid protein with multiple C2H2-type zinc-finger motifs. Although no highly homologous gene within the mammalian genome could not be detected using BLAST, a small sequence of similarity between the N-terminal zinc-finger motif of Chn and the fifth zinc-finger of human NRSF/REST was found. Chn has several structural and functional similarities to human NRSF/REST, as follows. First, Chn and NRSF/REST each contain an N-terminal region with multiple zinc-finger motifs (five motifs in 264 residues in Chn and eight motifs in 251 residues in NRSF/REST), followed by a cluster of S/T-P motifs (serine or threonine followed by a proline) and a single zinc-finger motif at the C terminus. Second, the C-terminal region of NRSF/REST binds a corepressor, CoREST, which serves as an adaptor molecule to recruit a complex that imposes silencing activities. The Drosophila homolog of CoREST (dCoREST) (Andres, 1999; Dallman, 2004) can associate with the C-terminal half of Chn in cultured S2 cells. Finally, NRSF/REST binds to NRSE/RE1, a 21-bp sequence located in the promoter region of many types of neuron-restricted genes, via the N-terminal zinc-finger motifs. It was found that a recombinant protein containing the N-terminal zinc-fingers of Chn bound specifically to the NRSE/RE1 sequence in vitro. Thus, the structural similarity to NRSF/REST, binding to dCoREST and the DNA-binding specificity of Chn suggest that it is a candidate for a functional Drosophila homolog of NRSF/REST (Tsuda, 2006).

If Chn acts as a regulator of neural-related functions, as suggested for NRSF/REST, then Chn would be expected to bind to a regulatory region common to many types of neural-related genes in Drosophila. Numerous sequences similar to NRSE/RE1 were identified in the Drosophila genome, and their binding to Chn was assessed by EMSA. Using these sequences, a consensus binding sequence for Chn (Chn-binding element (CBE), 5'-BBHASMVMMVCNGACVKNNCC-3') was derived. 26 CBEs were identified within 10 kb of annotated genes from the Drosophila genome. Binding to Chn was confirmed for 18 CBEs using EMSA competition assay. Genes containing the CBE include dopamine receptor 2 (DopR2) and the potassium channel, ether-a-go-go, for which the mammalian homologs are target genes of NRSF/REST. These results suggest that the CBE is a good indicator of Chn binding sites and that Chn regulates many types of neural-related genes, as is implicated for NRSF/REST. However, it was found that divergent forms of CBE adjacent to hairy and extramacrochaetae were bound specifically by Chn. Likewise, some of the CBE sites failed to bind to Chn. Thus, a further refinement will be necessary to predict a definitive set of Chn binding sites in the Drosophila genome (Tsuda, 2006).

Although it has been established that mammalian NRSF/REST is a key regulator of neuron-specific genes, attempts to isolate invertebrate homolog of NRSF/REST have so far failed to identify a true homologous factor in invertebrates. The properties of Chn, including the similarity in DNA-binding specificity, association with CoREST and transcriptional repressor activity, suggest that Chn is a strong candidate for a functional Drosophila homolog of NRSF/REST. chn was originally identified by its requirement in the development of the PNS. This study identified a number of candidate target genes of Chn, a large fraction of which is implicated in neural function and/or gene expression. It is expected that further analysis of these candidates will provide valuable information about chn function in vivo, which may be extended to the understanding of NRSF/REST (Tsuda, 2006).

The Chn mutation blocks eye development by preventing the initiation of MF, a process requiring Notch signaling. This phenotype is likely owing to a loss of Notch function, because elevated Dl expression is known to block Notch signaling. The function of Chn during the early stage of eye development might be to regulate Notch signaling at an appropriate level by downregulating Dl. It is possible that Chn-mediated modulation places a variety of Notch functions in eye under the influence of EGFR signaling and provides flexibility in its regulation (Tsuda, 2006).

Although chn is expressed in the MF, genetic analyses show that small clones of chn mutant cells permit progression of the MF and photoreceptor differentiation. It is speculated that the repressive effect of Chn is overcome by other signals in the MF, such as hedgehog signaling, which strongly induces Dl (Tsuda, 2006).

Developing photoreceptor cells are exposed to the EGFR ligand, Spitz, and the Notch ligand, Dl, and each cell must assess the level of the two signals and respond appropriately to perform each task of photoreceptor cell specification and induction of non-neural cone cells. This question was investigated by studying the expression of Dl in photoreceptor cells. chn was identified as a direct target of Ebi/SMRTER-dependent transcriptional repression and as a repressor of Dl expression. The abrogated expression of Dl in ebi mutants was recovered by reducing one copy of chn, suggesting that the negative regulation of chn by ebi is indeed prerequisite for photoreceptor cell development (Tsuda, 2006).

Genetic data suggest that Su(H) may activate or repress chn expression. This idea is supported by data showing that Ebi/SMRTER and NICD are recruited to the promoter region of chn. The Ebi/SMRTER complex formed in this region did not contain any detectable level of the intracellular domain of Notch (NICD), suggesting that the binding of Ebi/SMRTER and NICD to this region may be mutually exclusive, and therefore it is expected that a regulatory system controls the balance between the active and repressive states of Su(H). Taken together, these results suggest that chn is a key factor in the crosstalk between two major signal transduction pathways: the EGFR-dependent pathway and the Notch/Delta-dependent pathway (Tsuda, 2006).

In the mammalian system, competition between SMRT and NICD for interaction with RBPJkappa determines the state of RBPJkappa-dependent transcriptional activity. Extracellular signaling may modulate this competition; diverse signaling pathways modulate the functions of N-CoR/SMRT. The current findings would prompt investigations of potential interaction of two repression systems of NRSF/REST and N-CoR/SMRT, and their regulation by Notch and EGF signaling in mammalian neuronal differentiation (Tsuda, 2006).

A conserved role but different partners for the transcriptional corepressor CoREST in fly and mammalian nervous system formation

Identification of conserved proteins that act to establish the neuronal phenotype has relied predominantly on structural homologies of the underlying genes. In the case of the repressor element 1 silencing transcription factor (REST), a central player in blocking the neuronal phenotype in vertebrate non-neural tissue, the invertebrate homolog is absent, raising the possibility that distinct strategies are used to establish the CNS of invertebrates. Using a yeast two-hybrid screen designed specifically to identify functional analogs of REST, this study shows that Drosophila melanogaster uses a strategy that is functionally similar to, but appears to have evolved independently of, REST. The gene at the center of the strategy in flies encodes the repressor Tramtrack88 (Ttk88), a protein with no discernable homology to REST but that nonetheless is able to interact with the same transcriptional partners. Ttk88 uses the REST corepressor Drosophila CoREST to coordinately regulate a set of genes encoding the same neuronal hallmarks that are regulated by REST in vertebrates. These findings indicate that repression is an important mechanism for regulating neuronal phenotype across phyla and suggest that co-option of a similar corepressor complex occurred to restrict expression of genes critical for neuronal function to a compartmentalized nervous system (Dallman, 2004).

MicroRNA targeting of CoREST controls polarization of migrating cortical neurons

The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. The molecular basis of these changes remains elusive, and the present work describes how microRNAs (miRNAs) control neuronal polarization during radial migration. This study shows that miR-22 and miR-124 are expressed in the cortical wall where they target components of the CoREST/REST transcriptional repressor complex, thereby regulating doublecortin transcription in migrating neurons. This molecular pathway underlies radial migration by promoting dynamic multipolar-bipolar cell conversion at early phases of migration, and later stabilization of cell polarity to support locomotion on radial glia fibers. Thus, this work emphasizes key roles of some miRNAs that control radial migration during cerebral corticogenesis (Volvert, 2014)


REFERENCES

Search PubMed for articles about Drosophila CoRest

Abrajano, J. J., Qureshi, I. A., Gokhan, S., Zheng, D., Bergman, A. and Mehler, M. F. (2009a). Differential deployment of REST and CoREST promotes glial subtype specification and oligodendrocyte lineage maturation. PLoS One 4: e7665. PubMed ID: 19888342

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Abrajano, J. J., Qureshi, I. A., Gokhan, S., Molero, A. E., Zheng, D., Bergman, A. and Mehler, M. F. (2010). Corepressor for element-1-silencing transcription factor preferentially mediates gene networks underlying neural stem cell fate decisions. Proc Natl Acad Sci U S A 107: 16685-16690. PubMed ID: 20823235

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Curtis, B. J., Zraly, C. B., Marenda, D. R. and Dingwall, A. K. (2011). Histone lysine demethylases function as co-repressors of SWI/SNF remodeling activities during Drosophila wing development. Dev Biol 350: 534-547. PubMed ID: 21146519

Curtis, B. J., Zraly, C. B. and Dingwall, A. K. (2013). Drosophila LSD1-CoREST demethylase complex regulates DPP/TGFbeta signaling during wing development. Genesis 51: 16-31. PubMed ID: 22965777

Dallman, J. E., Allopenna, J., Bassett, A., Travers, A. and Mandel, G. (2004). A conserved role but different partners for the transcriptional corepressor CoREST in fly and mammalian nervous system formation. J Neurosci 24: 7186-7193. PubMed ID: 15306652

de la Calle-Mustienes, E., Modolell, J. and Gomez-Skarmeta, J. L. (2002). The Xiro-repressed gene CoREST is expressed in Xenopus neural territories. Mech Dev 110: 209-211. PubMed ID: 11744385

Di Stefano, L., Walker, J. A., Burgio, G., Corona, D. F., Mulligan, P., Naar, A. M. and Dyson, N. J. (2011). Functional antagonism between histone H3K4 demethylases in vivo. Genes Dev 25: 17-28. PubMed ID: 21205864

Domanitskaya, E. and Schupbach, T. (2012). CoREST acts as a positive regulator of Notch signaling in the follicle cells of Drosophila melanogaster. J Cell Sci 125: 399-410. PubMed ID: 22331351

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Fuentes, P., Canovas, J., Berndt, F. A., Noctor, S. C. and Kukuljan, M. (2012). CoREST/LSD1 control the development of pyramidal cortical neurons. Cereb Cortex 22: 1431-1441. PubMed ID: 21878487

Herz, H. M., Madden, L. D., Chen, Z., Bolduc, C., Buff, E., Gupta, R., Davuluri, R., Shilatifard, A., Hariharan, I. K. and Bergmann, A. (2010). The H3K27me3 demethylase dUTX is a suppressor of Notch- and Rb-dependent tumors in Drosophila. Mol Cell Biol 30: 2485-2497. PubMed ID: 20212086

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Lakowski, B., Roelens, I. and Jacob, S. (2006). CoREST-like complexes regulate chromatin modification and neuronal gene expression. J Mol Neurosci 29: 227-239. PubMed ID: 17085781

Lunyak, V. V., Burgess, R., Prefontaine, G. G., Nelson, C., Sze, S. H., Chenoweth, J., Schwartz, P., Pevzner, P. A., Glass, C., Mandel, G. and Rosenfeld, M. G. (2002). Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science 298: 1747-1752. PubMed ID: 12399542

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Tsuda, L., Kaido, M., Lim, Y. M., Kato, K., Aigaki, T. and Hayashi, S. (2006). An NRSF/REST-like repressor downstream of Ebi/SMRTER/Su(H) regulates eye development in Drosophila. EMBO J 25: 3191-3202. PubMed ID: 16763555

Volvert, M. L., Prevot, P. P., Close, P., Laguesse, S., Pirotte, S., Hemphill, J., Rogister, F., Kruzy, N., Sacheli, R., Moonen, G., Deiters, A., Merkenschlager, M., Chariot, A., Malgrange, B., Godin, J. D. and Nguyen, L. (2014). MicroRNA targeting of CoREST controls polarization of migrating cortical neurons. Cell Rep 7: 1168-1183. PubMed ID: 24794437

Wang, J., Scully, K., Zhu, X., Cai, L., Zhang, J., Prefontaine, G. G., Krones, A., Ohgi, K. A., Zhu, P., Garcia-Bassets, I., Liu, F., Taylor, H., Lozach, J., Jayes, F. L., Korach, K. S., Glass, C. K., Fu, X. D. and Rosenfeld, M. G. (2007). Opposing LSD1 complexes function in developmental gene activation and repression programmes. Nature 446: 882-887. PubMed ID: 17392792

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date revised: 17 January 2013

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