Epigenetic Silencing of Core Histone Genes by HERS in Drosophila

S, Itó; Fujiyama‐Nakamura, Sally; Kimura, Shuhei; Lim, Jinseon; Kamoshida, Yuki; Shiozaki-Sato, Yumi; Sawatsubashi, Shun; Suzuki, Eriko; Tanabe, Masahiko; Ueda, Takashi; Murata, Takuya; Kato, Hiromi; Ohtake, Fumiaki; Fujiki, Ryoji; Miki, Tsuneharu; Kouzmenko, Alexander; Takeyama, Ken-ichi; Kato, Shigeaki

doi:10.1016/j.molcel.2011.12.029

Cited by 22 publications

(20 citation statements)

References 52 publications

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“…However, it is unclear how core histone gene transcription is shut down early in S phase while the arrest of H1 transcription only occurs at the end of S phase. It has also been proposed that the DNA binding factor HERS silences histone gene transcription by formation of heterochromatin at the His-C locus toward the end of S phase (Ito et al, 2012). This mechanism, if involved, could not account for the early S phase silencing of the core histone genes, but could represent a more long-term silencing of the locus outside of S phase.…”

Section: Discussionmentioning

confidence: 99%

“…Why the H1 gene should utilize a distinct promoter recognition factor remained unclear. The silencing of histone genes at the end of S phase has recently been suggested to involve various mechanisms: the building of heterochromatin over the repeats (Ito et al, 2012), phosphorylation of H2B at Tyr37 upstream of the locus (Mahajan et al, 2012), and/or the binding of metabolic factors to single-stranded regions of His-C DNA (Kozhevnikova et al, 2012). Indeed, the Drosophila histone genes have been the subjects of numerous studies over the years, but to our knowledge, despite repeated efforts, including ours, none have successfully developed an in vitro transcription activation assay for the His genes.…”

Section: Introductionmentioning

confidence: 99%

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Gene-Specific Transcriptional Mechanisms at the Histone Gene Cluster Revealed by Single-Cell Imaging

2013

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To bridge the gap between in vivo and in vitro molecular mechanisms, we dissected the transcriptional control of the endogenous histone gene cluster (His-C) by single-cell imaging. A combination of quantitative immunofluorescence, RNA FISH, and FRAP measurements revealed atypical promoter recognition complexes and differential transcription kinetics directing histone H1 versus core histone gene expression. While H1 is transcribed throughout S phase, core histones are only transcribed in a short pulse during early S phase. Surprisingly, no TFIIB or TFIID was detectable or functionally required at the initiation complexes of these promoters. Instead, a highly stable, preloaded TBP/TFIIA "pioneer" complex primes the rapid initiation of His-C transcription during early S phase. These results provide mechanistic insights for the role of gene-specific core promoter factors and implications for cell cycle-regulated gene expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gene-Specific Transcriptional Mechanisms at the Histone Gene Cluster Revealed by Single-Cell Imaging

2013

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“…Since NPAT/Mxc does not bind DNA specifically, a likely possibility is recruitment to histone genes by interaction with a DNA binding protein. Another possibility is that a specific chromatin structure could be established on histone genes in both humans and flies that promotes recruitment of HLB components, including NPAT/Mxc 76,77 . Conserved sequences in the Drosophila H3/H4 promoter that are not present in the H2A/H2B promoter might serve to bind a specific factor or establish a specific chromatin structure.…”

Section: Self-organization Of the Hlbmentioning

confidence: 99%

Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

2017

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Metazoan replication-dependent (RD) histone genes encode the only known cellular mRNAs that are not polyadenylated. These mRNAs end instead in a conserved stem-loop, which is formed by an endonucleolytic cleavage of the pre-mRNA. The genes for all 5 histone proteins are clustered in all metazoans and coordinately regulated with high levels of expression during S phase. Production of histone mRNAs occurs in a nuclear body called the Histone Locus Body (HLB), a subdomain of the nucleus defined by a concentration of factors necessary for histone gene transcription and premRNA processing. These factors include the scaffolding protein NPAT, essential for histone gene transcription, and FLASH and U7 snRNP, both essential for histone pre-mRNA processing. Histone gene expression is activated by Cyclin E/Cdk2-mediated phosphorylation of NPAT at the G1-S transition. The concentration of factors within the HLB couples transcription with pre-mRNA processing, enhancing the efficiency of histone mRNA biosynthesis. KEYWORDSCell cycle; Drosophila; histone genes; mRNA processing; nuclear bodyProper utilization of genetic information in eukaryotes requires extensive three-dimensional organization of the genome and its associated proteins within the nucleus. The basic unit of genome organization is the nucleosome, an octamer of two molecules of each of the four core histone proteins (H2A, H2B, H3 and H4) that packages »147 base pairs of DNA. In mammalian cells, approximately 4£10 8 molcules of each core histone must be synthesized during S phase of the cell cycle to package the newly replicated DNA. Defects in this process result in genome instability that can contribute to human pathologies like cancer. Histone protein synthesis results from a large increase in production at the beginning of S phase of equal amounts of mRNAs encoding the four core nucleosomal histones, as well as histone H1. This highly coordinated gene expression event is performed by a set of transcription and pre-mRNA processing factors unique to replication dependent (RD) histone mRNA biosynthesis that assemble into a nuclear body tightly associated with RD histone genes called the histone locus body (HLB). HLB formation involves a combination of ordered and stochastic assembly steps, and cell cycle regulated changes in the HLB occur to activate histone gene expression during S phase. Here we describe the history of how the HLB was discovered followed by a discussion of HLB assembly mechanism and how the HLB functions in RD histone mRNA biosynthesis.

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“…In the S phase, nascent histone octamers stabilize daughter DNA into nucleosomal arrays for genomic DNA packing. [31][32][33] In addition to the canonical histone proteins, several non-canonical histone protein variants have been identified ( Figure 3). Significantly, genes encoding the non-canonical histones are not located in the canonical histone gene clusters, An epigenetic platform mutation in bone tumors S Kato et al and expression of the non-canonical histone variants is not coupled with DNA synthesis but resembles the pattern of housekeeping gene expression.…”

Section: Histone Variants As Functional Elements Of Epigenetic Machinerymentioning

confidence: 99%

Point mutations in an epigenetic factor lead to multiple types of bone tumors: role of H3.3 histone variant in bone development and disease

2015

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Coordinated post-translational modifications (PTMs) of nucleosomal histones emerge as a key mechanism of gene regulation by defining chromatin configuration. Patterns of histone modifications vary in different cells and constitute core elements of cell-specific epigenomes. Recently, in addition to canonical histone proteins produced during the S phase of cell cycle, several non-canonical histone variants have been identified and shown to express in a DNA replication-independent manner. These histone variants generate diversity in nucleosomal structures and add further complexity to mechanisms of epigenetic regulation. Cell-specific functions of histone variants remain to be determined. Several recent studies reported an association between some point mutations in the non-canonical histone H3.3 and particular types of brain and bone tumors. This suggests a possibility of differential physiological effects of histone variants in different cells and tissues, including bone. In this review, we outline the roles of histone variants and their PTMs in the epigenetic regulation of chromatin structure and discuss possible mechanisms of biological effects of the non-canonical histone mutations found in bone tumors on tumorigenesis in differentiating bone stem cells.

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Epigenetic Silencing of Core Histone Genes by HERS in Drosophila

Cited by 22 publications

References 52 publications

Gene-Specific Transcriptional Mechanisms at the Histone Gene Cluster Revealed by Single-Cell Imaging

Gene-Specific Transcriptional Mechanisms at the Histone Gene Cluster Revealed by Single-Cell Imaging

Coordinating cell cycle-regulated histone gene expression through assembly and function of the Histone Locus Body

Point mutations in an epigenetic factor lead to multiple types of bone tumors: role of H3.3 histone variant in bone development and disease

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