Following immunoscreening, a human cDNA encoding a novel member of the expanding helicase family has been cloned and sequenced. The deduced protein, designated hZFH (human zinc-finger helicase), contains the seven domains conserved among the helicase superfamily II and four potential zinc-fingers motifs. In particular, hZFH shows significant similarity to some proteins of the Snf2-like family, known to act as transcriptional regulators for multiples genes. Furthermore, hZFH has 68.5% identity to a human Mi-2 autoantigen to which autoantibodies are produced by a subgroup of patients affected by dermatomyositis. Northern-blot analyses have revealed several hZFH mRNAs with quantitative differences in various human tissues. One alternative splice site of hZFH mRNA was demonstrated and others were predicted. hZFH has been localized to 17p13-17p12 by in situ hybridization. Thus, this novel gene appears as a candidate for several malignant and genetic diseases associated with this region of the genome. The combination of these features suggests that hZFH plays an important role in gene regulation (Aubry, 1998).
Histone acetylation and deacetylation were found to be catalyzed by structurally distinct, multisubunit complexes that mediate, respectively, activation and repression of transcription. ATP-dependent nucleosome remodeling, mediated by different multisubunit complexes, was thought to be involved only in transcription activation. Reported here is the isolation of a protein complex that contains both histone deacetylation and ATP-dependent nucleosome remodeling activities. The complex contains the histone deacetylases HDAC1/2, histone-binding proteins, the dermatomyositis-specific autoantigen Mi2beta, a polypeptide related to the metastasis-associated protein 1, and a novel polypeptide of 32 kDa. Patients with dermatomyositis have a high rate of malignancy. The finding that Mi2beta exists in a complex containing histone deacetylase and nucleosome remodeling activities suggests a role for chromatin reorganization in cancer metastasis (Zhang, 1998).
A multi-subunit complex has been purified from Xenopus laevis eggs that contains six putative subunits including the known deacetylase subunits Rpd3 and RbAp48/p46 as well as substoichiometric quantities of the deacetylase-associated protein Sin3. In addition, one of the other components of the complex is Mi-2, a Snf2 superfamily member previously identified as an autoantigen in the human connective tissue disease dermatomyositis. Nucleosome-stimulated ATPase activity precisely copurifies with both histone deacetylase activity and the deacetylase enzyme complex. This association of a histone deacetylase with a Snf2 superfamily ATPase suggests a functional link between these two disparate classes of chromatin regulators (Wade, 1998).
Methylation of DNA at the dinucleotide CpG is essential for mammalian development and is correlated with stable transcriptional silencing. This transcriptional silencing has recently been linked at a molecular level to histone deacetylation through the demonstration of a physical association between histone deacetylases and the methyl CpG-binding protein MeCP2. A histone deacetylase complex from Xenopus laevis egg extracts consists of six subunits, including an Rpd3-like deacetylase, the RbA p48/p46 histone-binding protein and the nucleosome-stimulated ATPase Mi-2. Similar species have been isolated from human cell lines, implying functional conservation across evolution. This complex represents the most abundant form of deacetylase in amphibian eggs and cultured mammalian cells. The remaining three subunits of this enzyme complex have been identified. One of them binds specifically to methylated DNA in vitro and molecular cloning reveals a similarity to a known methyl CpG-binding protein. These data substantiate the mechanistic link between DNA methylation, histone deacetylation and transcriptional silencing (Wade, 1999).
ATP-dependent nucleosome remodeling and core histone acetylation and deacetylation represent mechanisms to alter nucleosome structure. NuRD is a multisubunit complex containing nucleosome remodeling and histone deacetylase activities. The histone deacetylases HDAC1 and HDAC2 and the histone binding proteins RbAp48 and RbAp46 form a core complex shared between NuRD and Sin3-histone deacetylase complexes. The histone deacetylase activity of the core complex is severely compromised. A novel polypeptide highly related to the metastasis-associated protein 1, MTA2, and the methyl-CpG-binding domain-containing protein, MBD3 (see Drosophila MBD-like), have been found to be subunits of the NuRD complex. MTA2 modulates the enzymatic activity of the histone deacetylase core complex. MBD3 mediates the association of MTA2 with the core histone deacetylase complex. MBD3 does not directly bind methylated DNA but is highly related to MBD2, a polypeptide that binds to methylated DNA and has been reported to possess demethylase activity. MBD2 interacts with the NuRD complex and directs the complex to methylated DNA. NuRD may provide a means of gene silencing by DNA methylation (Zhang, 1999).
Human p66alpha and p66beta are two potent transcriptional repressors that interact with the methyl-CpG-binding domain proteins MBD2 and MBD3. An analysis of the molecular mechanisms mediating repression resulted in the identification of two major repression domains in p66alpha and one in p66beta. Both p66alpha and p66beta are SUMO-modified in vivo: p66alpha at two sites (Lys-30 and Lys-487) and p66beta at one site (Lys-33). Expression of SUMO1 enhances the transcriptional repression activity of Gal-p66alpha and Gal-p66beta. Mutation of the SUMO modification sites or using a SUMO1 mutant or a dominant negative Ubc9 ligase results in a significant decrease of the transcriptional repression of p66alpha and p66beta. The Mi-2/NuRD components MBD3, RbAp46, RbAp48, and HDAC1 bind to both p66alpha and p66beta in vivo. Most of the interactions are not affected by the SUMO site mutations in p66alpha or p66beta, with two exceptions. HDAC1 binding to p66alpha is lost in the case of a p66alphaK30R mutant, and RbAp46 binding is reduced in the case of a p66betaK33R mutant. These results suggest that interactions within the Mi-2/NuRD complex as well as optimal repression are mediated by SUMOylation (Gong, 2006).
Production of the GTP-bound form of the Ran GTPase (RanGTP) around chromosomes induces spindle assembly by activating nuclear localization signal (NLS)-containing proteins. Several NLS proteins have been identified as spindle assembly factors, but the complexity of the process led to search for additional proteins with distinct roles in spindle assembly. This study identified a chromatin-remodeling ATPase, CHD4 (45% identical to Drosophila Mi2), as a RanGTP-dependent microtubule (MT)-associated protein (MAP). MT binding occurs via the region containing an NLS and chromatin-binding domains. In Xenopus egg extracts and cultured cells, CHD4 largely dissociates from mitotic chromosomes and partially localizes to the spindle. Immunodepletion of CHD4 from egg extracts significantly reduces the quantity of MTs produced around chromatin and prevents spindle assembly. CHD4 RNAi in both HeLa and Drosophila S2 cells induces defects in spindle assembly and chromosome alignment in early mitosis, leading to chromosome missegregation. Further analysis in egg extracts and in HeLa cells reveals that CHD4 is a RanGTP-dependent MT stabilizer. Moreover, the CHD4-containing NuRD complex promotes organization of MTs into bipolar spindles in egg extracts. Importantly, this function of CHD4 is independent of chromatin remodeling. These results uncover a new role for CHD4 as a MAP required for MT stabilization and involved in generating spindle bipolarity (Yokoyama, 2013).
The dynamic assembly and remodelling of eukaryotic chromosomes facilitate fundamental cellular processes such as DNA replication and gene transcription. The repeating unit of eukaryotic chromosomes is the nucleosome core, consisting of DNA wound about a defined octamer of histone proteins. Two enzymatic processes that regulate transcription by targeting elements of the nucleosome include ATP-dependent nucleosome remodelling and reversible histone acetylation. The histone deacetylases, however, are unable to deacetylate oligonucleosomal histones in vitro. The protein complexes that mediate ATP-dependent nucleosome remodelling and histone acetylation/deacetylation in the regulation of transcription were considered to be different, although it has recently been suggested that these activities might be coupled. The identification and functional characterization of a novel ATP-dependent nucleosome remodelling activity is reported that is part of an endogenous human histone deacetylase complex. This activity is derived from the CHD3 and CHD4 proteins that contain helicase/ATPase domains found in SWI2-related chromatin remodelling factors, and facilitates the deacetylation of oligonucleosomal histones in vitro. This complex is referred to as the nucleosome remodelling and deacetylating (NRD) complex. These results establish a physical and functional link between the distinct chromatin-modifying activities of histone deacetylases and nucleosome remodelling proteins (Tong, 1998).
ATP-dependent chromatin-remodeling complexes are known to facilitate transcriptional activation by opening chromatin structures. A novel human complex, named NURD, contains not only ATP-dependent nucleosome disruption activity, but also histone deacetylase activity, which usually associates with transcriptional repression. The deacetylation is stimulated by ATP on nucleosomal templates, suggesting that nucleosome disruption aids the deacetylase to access its substrates. One subunit of NURD was identified as MTA1, a metastasis-associated protein with a region similar to the nuclear receptor core-pressor, N-CoR; and antibodies against NURD partially relieve transcriptional repression by thyroid hormone receptor. These results suggest that ATP-dependent chromatin remodeling can participate in transcriptional repression by assisting repressors in gaining access to chromatin (Xue, 1998).
The Mi-2 complex has been implicated in chromatin remodeling and transcriptional repression associated with histone deacetylation. A purified Mi-2 complex containing six components (Mi-2, Mta 1-like, p66, RbAp48, RPD3, and MBD3) has been used to investigate the capacity of this complex to destabilize histone-DNA interactions and deacetylate core histones. The Mi-2 complex has ATPase activity that is stimulated by nucleosomes but not by free histones or DNA. This nucleosomal ATPase is relatively inefficient, yet is essential to facilitate both translational movement of histone octamers relative to DNA and the efficient deacetylation of the core histones within a mononucleosome. Surprisingly, ATPase activity has no effect on deacetylation of nucleosomal arrays (Guschin, 2000).
Histone deacetylation plays an important role in methylated DNA silencing. Recent studies indicated that the methyl-CpG-binding protein, MBD2, is a component of the MeCP1 histone deacetylase complex. Interestingly, MBD2 is able to recruit the nucleosome remodeling and histone deacetylase, NuRD, to methylated DNA in vitro. To understand the relationship between the MeCP1 complex and the NuRD complex, the MeCP1 complex was purified to homogeneity and it was found to contain 10 major polypeptides including MBD2 and all of the known NuRD components. Functional analysis of the purified MeCP1 complex revealed that it preferentially binds, remodels, and deacetylates methylated nucleosomes. Thus, this study defines the MeCP1 complex, and provides biochemical evidence linking nucleosome remodeling and histone deacetylation to methylated gene silencing (Feng, 2001).
MBD2 and MBD3 are two proteins that contain methyl-CpG binding domains and have a transcriptional repression function. Both proteins are components of a large CpG-methylated DNA binding complex named MeCP1, which consists of the nucleosome remodeling and histone deacetylase complex Mi2-NuRD and MBD2. MBD3L2 (methyl-CpG-binding protein 3-like 2) is a protein with substantial homology to MBD2 and MBD3, but it lacks the methyl-CpG-binding domain. Unlike MBD3L1, which is specifically expressed in haploid male germ cells, MBD3L2 expression is more widespread. MBD3L2 interacts with MBD3 in vitro and in vivo, co-localizes with MBD3 but not MBD2, and does not localize to methyl-CpG-rich regions in the nucleus. In glutathione S-transferase pull-down assays, MBD3L2 is found associated with several known components of the Mi2-NuRD complex, including HDAC1, HDAC2, MTA1, MBD3, p66, RbAp46, and RbAp48. Gel shift experiments with nuclear extracts and a CpG-methylated DNA probe indicate that recombinant MBD3L2 can displace a form of the MeCP1 complex from methylated DNA. MBD3L2 acts as a transcriptional repressor when tethered to a GAL4-DNA binding domain. Repression by GAL4-MBD3L2 is relieved by MBD2 and vice versa, and repression by MBD2 from a methylated promoter is relieved by MBD3L2. The data are consistent with a role of MBD3L2 as a transcriptional modulator that can interchange with MBD2 as an MBD3-interacting component of the NuRD complex. Thus, MBD3L2 has the potential to recruit the MeCP1 complex away from methylated DNA and reactivate transcription (Jin, 2005).
The Ikaros gene family encodes zinc finger DNA-binding proteins essential for lineage determination and control of proliferation in the lymphoid system. In the nucleus of a T cell, a major fraction of Ikaros and Aiolos proteins associate with the DNA-dependent ATPase Mi-2 and histone deacetylases, in a 2 MD complex. This Ikaros-NURD complex is active in chromatin remodeling and histone deacetylation. Upon T cell activation, Ikaros recruits Mi-2/HDAC to regions of heterochromatin. These studies reveal that Ikaros proteins are capable of targeting chromatin remodeling and deacetylation complexes in vivo. It is proposed that the restructuring of chromatin is a key aspect of Ikaros function in lymphocyte differentiation (Kim, 1999).
The lymphoid lineage-determining factors Ikaros and Aiolos can function as strong transcriptional repressors. This function is mediated through two repression domains and is dependent upon the promoter context and cell type. Repression by Ikaros proteins correlates with hypo-acetylation of core histones at promoter sites and is relieved by histone deacetylase inhibitors. Consistent with these findings, Ikaros and its repression domains can interact in vivo and in vitro with the mSin3 family of co-repressors, which bind to histone deacetylases. Based on these and the recent findings of associations between Ikaros and Mi-2-HDAC, it is proposed that Ikaros family members modulate gene expression during lymphocyte development by recruiting distinct histone deacetylase complexes to specific promoters (Koipally, 1999).
A SWI/SNF-related protein complex (PYR complex) has been described that is restricted to definitive (adult-type) hematopoietic cells and that specifically binds DNA sequences containing long stretches of pyrimidines. Deletion of an intergenic DNA-binding site for this complex from a human beta-globin locus construct results in delayed human gamma- to beta-globin switching in transgenic mice, suggesting that the PYR complex acts to facilitate the switch. PYR complex DNA-binding activity also copurifies with subunits of a second type of chromatin-remodeling complex, nucleosome-remodeling deacetylase (NuRD), that has been shown to have both nucleosome-remodeling and histone deacetylase activities. Gel supershift assays using antibodies to the ATPase-helicase subunit of the NuRD complex, Mi-2 (CHD4), confirm that Mi-2 is a component of the PYR complex. The hematopoietic cell-restricted zinc finger protein Ikaros copurifies with PYR complex DNA-binding activity, and antibodies to Ikaros also supershift the complex. NuRD and SWI/SNF components coimmunopurify with each other as well as with Ikaros. Competition gel shift experiments using partially purified PYR complex and recombinant Ikaros protein indicate that Ikaros functions as a DNA-binding subunit of the PYR complex. These results suggest that Ikaros targets two types of chromatin-remodeling factors -- activators (SWI/SNF) and repressors (NuRD) -- in a single complex (PYR complex) to the beta-globin locus in adult erythroid cells. At the time of the switch from fetal to adult globin production, the PYR complex is assembled and may function to repress gamma-globin gene expression and facilitate gamma- to beta-globin switching (O'Neill, 2000).
E7 is the main transforming protein of human papilloma virus type 16 (HPV16) which is implicated in the formation of cervical cancer. The transforming activity of E7 has been attributed to its interaction with the retinoblastoma (Rb) tumor suppressor. However, Rb binding is not sufficient for transformation by E7. Mutations within a zinc finger domain, which is dispensable for Rb binding, also abolish E7 transformation functions. HPV16 E7 has been shown to associate with histone deacetylase in vitro and in vivo, via its zinc finger domain. Using a genetic screen, Mi2beta, a component of the recently identified NURD histone deacetylase complex, has been identified as a protein that binds directly to the E7 zinc finger. A zinc finger point mutant that is unable to bind Mi2beta and histone deacetylase but is still able to bind Rb fails to overcome cell cycle arrest in osteosarcoma cells. These results suggest that the binding to a histone deacetylase complex is an important parameter for the growth promoting activity of the human papilloma virus E7 protein. This provides the first indication that viral oncoproteins control cell proliferation by targeting deacetylation pathways (Brehm, 1999).
Chromatin-modifying complexes are important for transcriptional control, but their roles in the regulation of development are poorly understood. Components of the nucleosome remodelling and histone deacetylase (NURD) complex antagonize vulval development, which is induced by the Ras signal transduction pathway. In three of the six equivalent vulval precursor cells, the Ras pathway is active, leading to the production of vulval fates; in the remaining three, the Ras pathway is inhibited and vulval fates repressed. Inhibition of Ras signaling occurs in part through the action of the synthetic multivulval (synMuv) genes, which comprise two functionally redundant pathways (synMuvA and synMuvB). Five C. elegans members of the NURD chromatin remodelling complex inhibit vulval development through both the synMuvA and synMuvB pathways [hda-1, rba-1 (a Caf-1 homolog), lin-53 (another Caf-1 homolog), chd-3 (an Mi-2 homolog) and chd-4]; another two members, the MTA1-related genes egr-1 and egl-27, act only in the synMuvA pathway. It is proposed that the synMuvA and synMuvB pathways function redundantly to recruit or activate a core NURD complex, which then represses vulval developmental target genes by local histone deacetylation. These results emphasise the importance of chromatin regulation in developmental decisions. Furthermore, inhibition of Ras signaling suggests a possible link between NURD function and cancer (Solari, 2000).
The Mi-2 protein is the central component of the recently isolated NuRD nucleosome remodelling and histone deacetylase complex. Although the NuRD complex has been the subject of extensive biochemical analyses, little is known about its biological function. The two C. elegans Mi-2 homologs, LET-418 and CHD-3, play essential roles during development. The two proteins possess both shared and unique functions during vulval cell fate determination, including antagonizm of the Ras signaling pathway required for vulval cell fate induction and the proper execution of the 2° cell fate of vulval precursor cells, a process under the control of LIN-12 Notch signaling. One of the C. elegans Mi-2 homologs, LET-418, plays a role in antagonizing the RTK/Ras/MAP kinase pathway via the synthetic multivulva (synMuv) pathway, supporting the recently proposed link between chromatin remodelling by NuRD-like complexes and the Ras signaling pathway. LET-418 and CHD-3 appear to have a shared role in the proper execution of the LIN-12 Notch dependent 2° cell fate of the P5.p and P7.p vulval precursor cells (von Zelewsky, 2000).
A rapid cascade of regulatory events defines the developmental fates of embryonic cells. However, once established, these developmental fates and the underlying transcriptional programs can be remarkably stable. Two proteins, MEP-1 and LET-418/Mi-2, are described that are required for maintenance of somatic differentiation in C. elegans. In animals lacking MEP-1 and LET-418, germline-specific genes become derepressed in somatic cells, and Polycomb group (PcG) and SET domain-related proteins promote this ectopic expression. MEP-1 and LET-418 interact in vivo with the germline-protein PIE-1. These findings support a model in which PIE-1 inhibits MEP-1 and associated factors to maintain the pluripotency of germ cells, while at later times MEP-1 and LET-418 remodel chromatin to establish new stage- or cell-type-specific differentiation potential (Unhavaithaya, 2002).
The predicted MEP-1 protein contains seven zinc-finger motifs. Each finger is comprised of a C(X)2C(X)10-12H(X)4H motif except for the third finger, which contains a cysteine residue in place of the terminal histidine. These features and a glutamine-rich sequence between the third and the fourth zinc-fingers are all well conserved in the predicted MEP-1 ortholog of Caenorhabditis brigsae, a sister nematode species, and in the protein product of the CG1244 gene in Drosophila. No other proteins in the current database show significant overall similarity to MEP-1 (Unhavaithaya, 2002).
To gain further insight into MEP-1 function, a rescuing GFP-tagged MEP-1 protein was immunoprecipitated from C. elegans extracts and associated proteins were analyzed using MALDI-TOF mass spectrometry. This analysis identified a 280 kDa protein, identified as the product of the gene let-418. LET-418 is a C. elegans homolog of Mi-2/CHD3, a core component of the conserved nucleosome remodeling and histone deacetylase (NURD) complex (Unhavaithaya, 2002).
The nuclear C2H2 zinc-finger protein MEP-1 inhibits the expression of germ-plasm components in somatic cells of C. elegans embryos and larvae. Embryos lacking MEP-1 protein complete embryogenesis but arrest development shortly after hatching and begin to express gene products normally restricted to the germline. In addition to LET-418, MEP-1 also interacts with HDA-1 the C. elegans ortholog of HDAC-1, a conserved histone deacetylase and NURD complex component. Taken together, these findings suggest an intriguing model for the developmental interactions between MEP-1, LET-418, and the MES proteins (C. elegans homologs of the PcG and TrxG groups of chromatin regulators). According to this model, stage-specific patterns of chromatin organization are established sequentially within each cell lineage in the developing animal through the concerted action of transcriptional activators and repressors. Maintenance of these domains in the germline is controlled at least in part through the action of the MES proteins, while other PcG- and TrxG-related proteins may serve this function in other tissues. The MEP-1 and LET-418 proteins are proposed to function along with HDA-1 and, perhaps, with other components of the NURD complex at or after the onset of succeeding differentiation events to modify the distribution of these maintenance factors and thereby to allow the stable specification of new stage-specific chromatin domains (Unhavaithaya, 2002).
Experiments in Xenopus have illustrated the importance of extracellular morphogens for embryonic gene regulation in vertebrates. Much less is known about how induction leads to the correct positioning of boundaries; for example, between germ layers. This study reports that the neuroectoderm/mesoderm boundary is controlled by the chromatin remodeling ATPase CHD4/Mi-2β. Gain and loss of CHD4 function experiments shifted this boundary along the animal-vegetal axis at gastrulation, leading to excess mesoderm formation at the expense of neuroectoderm, or vice versa. This phenotype results from specific alterations in gene transcription, notably of the neural-promoting gene Sip1 and the mesodermal regulatory gene Xbra. CHD4 suppresses Sip1 transcription by direct binding to the 5' end of the Sip1 gene body. Furthermore, CHD4 and Sip1 expression levels determine the 'ON' threshold for Nodal-dependent but not for eFGF-dependent induction of Xbra transcription. The CHD4/Sip1 epistasis thus constitutes a regulatory module, which balances mesoderm and neuroectoderm formation (Linder, 2007).
Freshwater planarians are able to regenerate any missing part of their body and have extensive tissue turnover because of the action of dividing cells called neoblasts. Neoblasts provide an excellent system for in vivo study of adult stem cell biology. This study identified the Smed-CHD4 gene, which is predicted to encode a chromatin-remodeling protein similar to CHD4/Mi-2 proteins, as required for planarian regeneration and tissue homeostasis. Following inhibition of Smed-CHD4 with RNA interference (RNAi), neoblast numbers were initially normal, despite an inability of the animals to regenerate. However, the proliferative response of neoblasts to amputation or growth stimulation in Smed-CHD4(RNAi) animals was diminished. Smed-CHD4(RNAi) animals displayed a dramatic reduction in the numbers of certain neoblast progeny cells. Smed-CHD4 ks required for the formation of these neoblast progeny cells. Together, these results indicate that Smed-CHD4 is required for neoblasts to produce progeny cells committed to differentiation in order to control tissue turnover and regeneration and suggest a crucial role for CHD4 proteins in stem cell differentiation (Scimone, 2010).
Changes in chromatin structure have been implicated in the regulation and maintenance of many cell fate decisions. Chromatin modifiers can be essential to keep stem cells in a pluripotent stage or to drive them into a differentiation pathway. For example, in the case of mouse and human embryonic stem (ES) cells, components of the polycomb complex can silence developmental regulatory genes that are preferentially expressed during differentiation. These results suggest that polycomb proteins maintain the pluripotent state of ES cells. Ezh, a component of the PRC2 polycomb complex, is also active in epidermal progenitors. However, in general, how the regulation of differentiation in ES cells corresponds to what occurs in adult stem cell types in vivo remains unresolved. In the case of the NuRD complex component CHD4, the current data indicate a role in promoting, rather than repressing, stem cell differentiation. The NuRD complex has been shown to regulate cell fate decisions and development in multiple contexts. In D. melanogaster for example, Mi-2 can function with polycomb genes to maintain repression of homeotic genes during embryonic patterning. In C. elegans, the CHD4 homolog let-418, is required for vulval cell fate determination and for maintenance of germline-soma distinctions. Specifically, in let-418-defective animals, somatic cells express germ cell markers (e.g. the P granule component PGL-1 and Vasa homologs), indicating that a CHD4 protein in C. elegans is required to repress germline cell identity in differentiated cells. Interestingly, a CHD4 homolog in the plant A. thaliana, pickle, is required for repression of embryonic-like characteristics after germination. In pickle mutants, the fatty acid composition of roots was shown to resemble that of seeds, and roots formed callus growths and embryo-like physical structures. Therefore, in both C. elegans and Arabidopsis, these data suggest a function in repression of germ cell/embryonic-like features in differentiated tissue. It will be interesting to determine in the future how these roles compare with the action of CHD4 in stem cells in other organisms. For instance, it is possible that CHD4 represses stem cell/embryonic-like genes in differentiated tissues in these organisms and in planarian neoblasts to promote neoblast differentiation (Scimone, 2010).
In the mouse, knockout of Mi-2β (CHD4) has complex impacts on the functioning of hematopoietic stem cells (HSCs). Mi-2β-deficient HSCs displayed increased proliferation and were able to begin differentiation into erythroid, but not myeloid and lymphoid, lineages. Specifically, conditional knockout Mi-2δ animals showed depletion of granulocytes (myeloid) and newly formed B cells (lymphocytes). Furthermore, although pro-erythroblasts were formed, the differentiation of these pro-erythroblasts into basophilic and other cells was aberrant in these mice. Therefore, in the case of this stem cell type, Mi-2δ appears to be required for lineage decisions that could reflect a role in differentiation. Expression analyses indicated that Mi-2δ did not play a global role in gene expression regulation but affected specific transcripts. The gene expression defects in these Mi-2δ-deficient HSCs also indicated a potential additional role for Mi-2δ in self-renewal. A different component of the NuRD complex, Mbd3, was found to be required for ES cells to differentiate in vitro; Mbd3 was also required for proliferation of epiblast cells in culture and derivation of ES cells from inner-cell-mass cells. The data from adult planarian neoblasts described here, taken in the context of the results describing the function of CHD4 and other NuRD components in other organisms, suggest that a major and broadly utilized role for this complex is in promoting stem cell differentiation (Scimone, 2010).
Home page: The Interactive Fly © 1995, 1996 Thomas B. Brody, Ph.D.
The Interactive Fly resides on the
Society for Developmental Biology's Web server.