Therefore, regulatory sequences appear to be common in the nucleosomal core histone gene loci to ensure their synchronized expression (Ito, 2012). Coordinated protein production is required for all of the canonical core histones to produce optimal amounts of histone octamers in response to cellular requirements. 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. 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. 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. Unlike the vast majority of the genes transcribed by RNA polymerase II, multiple copies of the histone genes are organized in gene clusters. The genes encoding canonical histones (H1, H2A, H2B, H3, and H4) are present in multiple copies and transcriptionally inactive in the quiescent cell state. It is now accepted that histone proteins play a prime role in epigenetic regulation, serving as substrates for chromatin modifications (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). These findings illustrate a salient molecular switch linking epigenetic gene silencing to cell cycle-dependent histone production (Ito, 2012). 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. HERS protein is phosphorylated by a cyclin-dependent kinase (Cdk) at the end of S-phase. 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. However, the molecular basis of cell cycle-dependency in the switching of histone gene regulation remains to be uncovered. It should be pointed out that these factors are unlikely to be the thus-far described neuronal precursor genes, as mutations in these genes do not result in any obvious cell cycle defects (Hassan, 1997).Įpigenetic Silencing of Core Histone Genes by HERS in DrosophilaĬell cycle-dependent expression of canonical histone proteins enables newly synthesized DNA to be integrated into chromatin in replicating cells. Sensory organ precursors lacking Da may fail to express and/or accumulate other factors, such as critical differentiation genes, required for SOP entry into the cell cycle. This suggests thatĪll aspects of PNS precursor differentiation examined so far are under the transcriptional control of da. Precursors are still present at these stages in da mutants. Cyclin A, barren, disc proliferation abnormal and Histone H1 transcripts are significantly reduced or undetectable in the precursors of the PNS at stages 11 and 12. Various stages of the cell cycle are misexpressed in the PNS of da mutant embryos. Four genes whose products are required for Undergo a normal cell cycle and divide in da mutants. These findings, however, do not explain the failure of the nascent PNS precursors to These genes are required for differentiation and cell fate determination in theĭeveloping PNS. Previous studies have shown that the ubiquitously expressed Da protein is required for the properĮxpression of neuronal precursor genes and lineage identity genes in the PNS of DrosophilaĮmbryos. Of neuronal lineage development in all peripheral nervous system (PNS) lineages following the selection of neuronal precursor cells. The function of the neuronal differentiation gene daughterless is required for the proper initiation
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