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Dynamic incorporation of histone H3 variants into chromatin is essential for acquisition of aggressive traits and metastatic colonization [ATAC-seq]

ABSTRACT: Metastasis is the leading cause of cancer mortality. Chromatin remodeling is crucial for metastasis formation, laying the ground for the cellular reprogramming necessary to drive metastasis. However, little is known about the nature of this remodeling and its regulation. Here, we show that metastasis-inducing pathways regulate histone chaperones to reduce canonical histone incorporation into chromatin, triggering deposition of H3.3 variant at the promoters of poor-prognosis genes and metastasis-inducing transcription factors. This specific incorporation of H3.3 into chromatin is both necessary and sufficient for the induction of aggressive traits that allow for metastasis formation. Together, our data clearly show histone variant H3.3 as a major regulator of cell fate during tumorigenesis, and histone chaperones as valuable therapeutic targets for invasive carcinomas.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132046 | GEO | 2019/09/03

REPOSITORIES: GEO

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Dynamic incorporation of histone H3 variants into chromatin is essential for acquisition of aggressive traits and metastatic colonization

Project description:Carcinomas can acquire metastatic potential by undergoing a cellular program referred to as epithelial-to-mesenchymal transition (EMT). During EMT, the genome undergoes major epigenetic changes required for the expression of genes that promote cell motility, invasiveness, and survival under stress. While recent data point to a crucial role of chromatin remodeling in this process, little is known about the nature of this remodeling and the signals that trigger it. Here we show that metastasis-inducing pathways regulate histone chaperones to reduce canonical histone incorporation into chromatin. This triggers deposition of H3.3 to the promoters of EMT-inducing transcription factors and poor prognosis genes, a phenomenon that is sufficient and necessary for the induction of EMT and metastasis. Together, we have discovered histone H3.3 variant as a major regulator of cell fate during tumorigenesis and histone chaperones as valuable therapeutic targets for metastatic disease.

2019-09-03 | GSE120313 | GEO

Dynamic incorporation of histone H3 variants into chromatin is essential for acquisition of aggressive traits and metastatic colonization

2019-09-02 | GSE119030 | GEO

Factors influencing in vivo deposition of histone variants H3.1 and H3.3

Project description:Establishment of a proper chromatin landscape is central to genome function. Here, we explain H3 variant distribution by specific targeting and dynamics of deposition involving the CAF-1 and HIRA histone chaperones. Impairing replicative H3.1 incorporation via CAF-1 enables an alternative H3.3 deposition at replication sites via HIRA. Conversely, the H3.3 incorporation throughout the cell cycle via HIRA cannot be replaced by H3.1. ChIP-seq analyses reveal correlation between HIRA-dependent H3.3 accumulation and RNA pol II at transcription sites and specific regulatory elements, further supported by their biochemical association. Remarkably, the HIRA complex shows unique DNA binding properties and depleting HIRA increases DNA sensitivity to nucleases. We propose that protective gap-filling of naked DNA by HIRA leads to a broad distribution of H3.3, and HIRA association with Pol II ensures local H3.3 enrichment at specific sites. Examination of genome-wide localization of two histone H3 variants.

2011-12-16 | E-GEOD-31794 | biostudies-arrayexpress

Genome-wide incorporation dynamics reveal distinct categories of turnover for the histone variant H3.3

Project description:We developed a system to study the DNA replication-independent turnover nucleosomes containing the histone variant H3.3 in mammalian cells. By measuring the genome-wide incorporation of H3.3 at different time points following epitope-tagged H3.3 expression, we find three categories of H3.3-nucleosome turnover in vivo: rapid turnover, intermediate turnover and, specifically at telomeres, slow turnover. Our data indicate that H3.3-containing nucleosomes at enhancers and promoters undergo a rapid turnover that is associated with active histone modification marks including H3K4me1, H3K4me3, H3K9ac, H3K27ac and the histone variant H2A.Z. The rate of turnover is negatively correlated with H3K27me3 at regulatory regions and with H3K36me3 at gene bodies. Examination of incorporation dynamics of histone variant H3.3

2013-10-23 | E-GEOD-51505 | biostudies-arrayexpress

Histone H3.3 fills gaps in heterochromatin generated by Smarcad1 in mouse embryonic stem cells (ESC)

Project description:Nucleosome turnover concomitant with incorporation of the replication-independent histone variant H3.3 is a hallmark of regulatory regions in the animal genome. In our current understanding, nucleosome turnover is universally linked to DNA accessibility and histone acetylation. In mouse embryonic stem cells, H3.3 is also highly enriched at interstitial heterochromatin, most prominently intracisternal-A particle endogenous retroviral elements. Interstitial heterochromatin is established over confined domains by the TRIM28/SETDB1 corepressor complex and has stereotypical features of repressive chromatin, such as H3K9me3 and recruitment of all HP1 isoforms. Here, we demonstrate that fast histone turnover and H3.3 incorporation is compatible with these hallmarks of heterochromatin. We identify Smarcad1 to be a chromatin remodeler that generates nucleosome-free regions which are subsequently filled with histone H3.3, generating a surprisingly dynamic heterochromatin state. Loss of histone H3.3 elicits a highly specific opening of interstitial heterochromatin demonstrating that in the wake of Smarcad1 remodeling, H3.3 is required to maintain minimal DNA accessibility by reassembling nucleosomes.

2020-08-28 | GSE149080 | GEO

Multilevel interrogation of H3.3 dynamics reveals a primordial role in transcription regulation in Tetrahymena [RNA-seq]

Project description:Through epigenetic modifications and selective incorporation of histone variants into chromatin, eukaryotic cells can adjust their transcriptional profile in response to molecular needs. We used the nuclear dimorphic ciliate protozoan, Tetrahymena thermophila, as a model system to investigate the dynamics of H3 variant function. H3.3 is the ancestral H3 variant with key roles in regulating chromatin states and transcription. Functional proteomics and immunofluorescence analyses of H3.1 and H3.3 revealed a conserved role for Nrp1 and Asf1 histone chaperones in nuclear influx of histones. Cac2 and Hir1 have distinct localization patterns during different stages of the Tetrahymena life cycle and suggests that both Cac2 and Hir1 might be dispensable for the replication-dependent and -independent deposition of H3.1 and H3.3, respectively. ChIP-seq experiments in growing Tetrahymena show H3.3 enrichment over promoters, genes bodies, and transcription termination sites of highly transcribed genes. H3.3 knockout followed by RNA-seq reveals large-scale transcriptional alterations in functionally important genes. Our results provide an evolutionary perspective on H3.3’s conserved role in maintaining the transcriptional landscape of cells and on the emergence of specialized chromatin assembly pathways.

2023-04-03 | GSE210902 | GEO

Multilevel interrogation of H3.3 dynamics reveals a primordial role in transcription regulation in Tetrahymena [ChIP-seq]

2023-04-03 | GSE210901 | GEO

Factors influencing in vivo deposition of histone variants H3.1 and H3.3

2011-12-16 | GSE31794 | GEO

Histone H3.3 is required for endogenous retroviral element silencing and genome stability [RNA-Seq]

Project description:Endogenous retroviruses (ERVs) have provided an evolutionary advantage in the diversification of transcript regulation and are thought to be involved in the establishment of extraembryonic tissues during development. However, silencing of these elements remains critical for the maintenance of genome stability. Here, we define a new chromatin state that is uniquely characterized by the combination of the histone variant H3.3 and H3K9me3, two chromatin ‘marks’ that have previously been considered to belong to fundamentally opposing chromatin states. H3.3/H3K9me3 heterochromatin is fundamentally distinct from ‘canonical’ H3K9me3 heterochromatin that has been under study for decades and this unique functional interplay of a histone variant and a repressive histone mark is crucial for silencing ERVs in ESCs. Our study solidifies the emerging notion that H3.3 is not a histone variant associated exclusively with “active” chromatin and further suggests that its incorporation at unique heterochromatic regions may be central to its function during development and the maintenance of genome stability. RNA-seq analysis of three embryonic stem cell lines WT, H3.3 KO1, and H3.3 KO2)

2015-05-05 | E-GEOD-59104 | biostudies-arrayexpress

HIRA-mediated loading of histone variant H3.3 controls androgen-induced transcription by regulation of AR/BRD4 complex assembly at enhancers [ATAC-Seq]

Project description:To study the function of histone variant H3.3 pathway in androgen receptor-driven transcription in prostate cancer (PCa) we knocked out androgen receptor (AR) and H3.3 chaperones HIRA and DAXX in R1-AD1 (wild type AR) and R1-D567 (deltaLBD AR) cell lines. Integrative analysis with RNA-seq, ChIP-seq and ATAC-seq revealed that HIRA KO deregulates androgen-induced gene expression in PCa by reducing H3.3 incorporation, diminishing H3.3S31Ph and H3K27Ac, thus modifying recruitment of BRD4 and altering AR binding within enhancers of target genes.

2023-11-02 | GSE230529 | GEO

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