Histone gene-specific Epigenetic Repressor in late S phase: Biological Overview | References
Gene name - Histone gene-specific Epigenetic Repressor in late S phase
Synonyms - CG32529
Cytological map position - 18F4-19A2
Function - chromatin component
Keywords - Repressor in late S phase histone transcription, cell cycle dependent gene silencing
Symbol - Hers
FlyBase ID: FBgn0052529
Genetic map position - chrX:19762482-19800835
Classification - Bromo adjacent homology domain
Cellular location - nuclear
Cell cycle-dependent expression of canonical histone proteins enables newly synthesized DNA to be integrated into chromatin in replicating cells. However, the molecular basis of cell cycle-dependency in the switching of histone gene regulation remains to be uncovered. This study reports the identification and biochemical characterization of a molecular switcher, HERS (histone gene-specific epigenetic repressor in late S phase), for nucleosomal core histone gene inactivation in Drosophila. HERS protein is phosphorylated by a cyclin-dependent kinase (Cdk) at the end of S-phase. Phosphorylated HERS binds to histone gene regulatory regions and anchors HP1 and Su(var)3-9 to induce chromatin inactivation through histone H3 lysine 9 methylation. These findings illustrate a salient molecular switch linking epigenetic gene silencing to cell cycle-dependent histone production (Ito, 2012).
Histones are fundamental components of chromatin that maintain and regulate appropriate chromatin conformation to support all genomic DNA-dependent processes, including transcription, replication, repair, and mitosis). It is now accepted that histone proteins play a prime role in epigenetic regulation, serving as substrates for chromatin modifications (Ito, 2012).
The genes encoding canonical histones (H1, H2A, H2B, H3, and H4) are present in multiple copies and transcriptionally inactive in the quiescent cell state. Unlike the vast majority of the genes transcribed by RNA polymerase II, multiple copies of the histone genes are organized in gene clusters. In Drosophila, the histone gene cluster is composed of about 100 copies of tandemly arranged nucleosomal core (H2A, H2B, H3, and H4) and linker (H1) histone gene cassettes. The histone gene cluster is localized at a subnuclear compartment, histone locus body (HLB) that is presumed to contain factors essential for coordinated regulation of all histone gene copies (Nizami, 2010; White, 2011). In early S phase of the cell cycle, histone genes are activated to supply histone proteins for the integration of newly synthesized DNA into nucleosomes (De Koning, 2007; Groth, 2007). Coordinated protein production is required for all of the canonical core histones to produce optimal amounts of histone octamers in response to cellular requirements. Therefore, regulatory sequences appear to be common in the nucleosomal core histone gene loci to ensure their synchronized expression (Ito, 2012).
The cell cycle-dependent expression of canonical histones might be achieved through conserted action of cell-cycle, phase-specific nuclear factors at multiple levels of regulation. Recent studies have shown that the nuclear protein ataxia-telangiectasia locus (NPAT) plays a key role in the induction of histone genes. NPAT associates with histone loci and is functionally activated in early S phase by cyclin-dependent kinase 2 (Cdk2)/cyclin E (CycE), a kinase complex known to promote G1/S transition. Recently, fly homeotic gene mxc was identified as Drosophila NPAT ortholog (Rajendra, 2010; White, 2011). At the end of S phase, histone gene transcription is rapidly turned down and histone mRNAs are destabilized, ending the histone protein production. Although it has been assumed that dephosphorylation of NPAT is critical for histone gene silencing, the mechanisms of transcriptional suppression of histone genes remain to be identified (Ito, 2012).
During genetic screening of transcriptional coregulators in Drosophila, a critical factor has been identified that switched off nucleosomal core histone gene expression at the end of S phase through epigenetic inactivation of chromatin. Therefore, this factor was designated histone gene-specific epigenetic repressor in late S-phase (HERS) and presumed to function as a repressor of canonical core histone gene loci (Ito, 2012).
In contrast to NPAT, HERS protein abundance appears to be cell cycle-dependent because HERS was undetectable at the G1/S transition and only emerged in late S phase. Cdk-dependent phosphorylation of HERS is required for its association with core histone gene regulatory regions through sequence-specific DNA binding. This study has identified Cdk1/CycA as a prospective kinase complex that may phosphorylate HERS in vivo. However, because it has not been confirmed whether the Cdk1 inhibitor that was used here does not affect Drosophila Cdk2 or Cdk1/CycB activities, the possibility cannot be excluded that these Cdk complexes may also phosphorylate HERS. Owing to the cell cycle-specific expression and phosphorylation of HERS, its localization on the HIS-C appears to be limited to the completion of replication in the late S phase. This is further supported by HERS localization on the histone gene loci in the polytene chromosomes of salivary glands, in which DNA replication is completed and histone genes are inactive. Moreover, phosphorylation also significantly enhances HERS protein stability. Therefore, it is conceivable that dephosphorylation terminates HERS action and targets the protein for degradation (Ito, 2012).
HERS shuts down core histone gene expression through recruitment of the Su(var)3-9/HP1 repressor complex, a universal and normally abundant epigenetic silencer. Molecular interaction has been confirmed only between HERS and Su(var)3-9 but not with other tested H3K9 methyltransferases, G9a and dSETDB1, although genetic interaction of HERS was also observed with G9a and dSETDB1 in the Drosophila experimental system. It has been proposed that histone H3K9-specific methyltransferases function independently at their target loci, whereas they act in a sequential manner at the same gene locus (Brower-Toland, 2009). Moreover, it has been reported that G9a and dSETDB1 are active in early development, whereas Su(var)3-9 predominantly acts from early embryogenesis to later stages of Drosophila development. Thus, the possibility cannot be excluded that other histone H3K9 methyltransferases may also support HERS function (Ito, 2012).
The motif organization of HERS protein is atypical compared to other reported cell-cycle regulators. Even though phosphorylated HERS appears to act as a DNA binding factor, it lacks known motifs associated with DNA binding, protein-protein interaction, or other molecular interactions. Instead, this protein encompasses only one known motif, the BAH domain. The BAH domain is present in many chromatin-related regulators, including ORC1, polybromo, DNMT1, and yeast Sir3. The only reported role for the BAH domains in yeast Sir3 and Orc1 is that of nonselective association with nucleosomes. Although functional and physical interactions of the BAH domains were assessed for different histones modified at particular residues (for example, H3K9 methylation), it has not yet been possible to delineate any specific role of the HERS BAH domain at this stage. Nevertheless, it is conceivable that nonselective association with nucleosomes through the BAH domain may facilitate or stabilize HERS binding to specific regulatory DNA sequences in histone gene loci (Ito, 2012).
Although it remains unclear whether Drosophila HERS acts as a regulator of other cellular events, it was found that HERS knockdown in insect S2 cells resulted in cell-cycle arrest at the G2/M phase. Furthermore, when HERS was overexpressed in mammalian cell lines (HEK293 and Y1 cells), cell-cycle arrest was observed together with polyploidy. Besides other possible implications, this suggests an existence of mammalian HERS homolog(s). Interestingly, several uncharacterized mammalian proteins bearing the BAH domain have been documented. As mammals have three HP1 protein family members (α, β, and γ) with different functions, it is conceivable that mammalian HERS may consist of multiple members or isoforms with distinct cellular functions (Ito, 2012).
Search PubMed for articles about Drosophila Hers
Brower-Toland, B., et al. (2009). Multiple SET methyltransferases are required to maintain normal heterochromatin domains in the genome of Drosophila melanogaster. Genetics 181: 1303-1319. PubMed ID: 19189944
De Koning, L., et al. (2007). Histone chaperones: an escort network regulating histone traffic Nat. Struct. Mol. Biol. 14: 997-1007. PubMed ID: 17984962
Groth, A., Rocha, W., Verreault, A. and Almouzni, G. (2007). Chromatin challenges during DNA replication and repair. Cell 128: 721-733. PubMed ID: 17320509
Ito, S., Fujiyama-Nakamura, S., Kimura, S., Lim, J., Kamoshida, Y., Shiozaki-Sato, Y., Sawatsubashi, S., Suzuki, E., Tanabe, M., Ueda, T., Murata, T., Kato, H., Ohtake, F., Fujiki, R., Miki, T., Kouzmenko, A., Takeyama, K., Kato, S. (2012). Epigenetic Silencing of Core Histone Genes by HERS in Drosophila. Mol. Cell 45(4): 494-504. PubMed ID: 22365829
Nizami, Z., Deryusheva, S. and Gall, J. G. (2010). The Cajal body and histone locus body Cold Spring Harb. Perspect. Biol, 2: a000653. PubMed ID: 20504965
Rajendra, T. K., Praveen, K. and Matera, A. G. (2010). Genetic analysis of nuclear bodies: from nondeterministic chaos to deterministic order. Cold Spring Harb. Symp. Quant. Biol. 75: 365-374. PubMed ID: 21467138
White, W. E., et al. (2011). Drosophila histone locus bodies form by hierarchical recruitment of components. J. Cell Biol. 193: 677-694. PubMed ID: 21576393
date revised: 10 August 2012
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