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Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE125221 | GEO | 2022/09/01

REPOSITORIES: GEO

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Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies [ATAC-Seq]

Project description:Mutations in the BAF chromatin remodeling complex rank among the most frequent genetic alterations in human cancers, many of which result in a loss of function of the respective subunits. Recent genomic and chemical screens have revealed synthetic lethal interactions of BAF complex subunits with each other as well as with further chromatin modifiers. Using an epigenome-focused shRNA library, we identified loss of the histone chaperone complex CAF-1 (chromatin assembly factor 1) as a synthetic lethal vulnerability of ARID1A-deficient cells that is enhanced by the androgen receptor agonist testosterone. In line with antagonistic roles of the CAF-1 and BAF complexes in nucleosome deposition and remodeling, we show that knock-down of CAF-1 subunits results in a partial reversal of the transcriptional and chromatin accessibility effects caused by loss of ARID1A. Together, our findings identify a new functional partner of the BAF chromatin remodeling complex and represent a potential novel strategy for targeting ARID1A-deficient cancers.

2022-09-01 | GSE125220 | GEO

Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies [RNA-Seq]

2022-09-01 | GSE125219 | GEO

Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies

Project description:Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies

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Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies [RNA-Seq]

Project description:Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies [RNA-Seq]

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Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies [ATAC-Seq]

Project description:Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies [ATAC-Seq]

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The histone chaperone CAF-1 safeguards somatic cell identity.

Project description:Cellular differentiation involves profound remodelling of chromatic landscapes, yet the mechanisms by which somatic cell identity is subsequently maintained remain incompletely understood. To further elucidate regulatory pathways that safeguard the somatic state, we performed two comprehensive RNA interference (RNAi) screens targeting chromatin factors during transcription-factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPS cells). Subunits of the chromatin assembly factor-1 (CAF-1) complex, including Chaf1a and Chaf1b, emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation and heterochromatin maintenance. Optimal modulation of both CAF-1 and transcription factor levels increased reprogramming efficiency by several orders of magnitude and facilitated iPS cell formation in as little as 4 days. Mechanistically, CAF-1 suppression led to a more accessible chromatin structure at enhancer elements early during reprogramming. These changes were accompanied by a decrease in somatic heterochromatin domains, increased binding of Sox2 to pluripotency-specific targets and activation of associated genes. Notably, suppression of CAF-1 also enhanced the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 to be a novel regulator of somatic cell identity during transcription-factor-induced cell-fate transitions and provide a potential strategy to modulate cellular plasticity in a regenerative setting.

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The Cac1 subunit of histone chaperone CAF-1 organizes CAF-1-H3/H4 architecture and tetramerizes histones.

Project description:The histone chaperone Chromatin Assembly Factor 1 (CAF-1) deposits tetrameric (H3/H4)2 histones onto newly-synthesized DNA during DNA replication. To understand the mechanism of the tri-subunit CAF-1 complex in this process, we investigated the protein-protein interactions within the CAF-1-H3/H4 architecture using biophysical and biochemical approaches. Hydrogen/deuterium exchange and chemical cross-linking coupled to mass spectrometry reveal interactions that are essential for CAF-1 function in budding yeast, and importantly indicate that the Cac1 subunit functions as a scaffold within the CAF-1-H3/H4 complex. Cac1 alone not only binds H3/H4 with high affinity, but also promotes histone tetramerization independent of the other subunits. Moreover, we identify a minimal region in the C-terminus of Cac1, including the structured winged helix domain and glutamate/aspartate-rich domain, which is sufficient to induce (H3/H4)2 tetramerization. These findings reveal a key role of Cac1 in histone tetramerization, providing a new model for CAF-1-H3/H4 architecture and function during eukaryotic replication.

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Synthetic Lethal Interactions for Kinase Deficiencies to DNA Damage Chemotherapeutics.

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The histone chaperone CAF-1 safeguards somatic cell identity during transcription factor-induced reprogramming

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-12-10 | E-GEOD-66534 | biostudies-arrayexpress

ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A.

Project description:Identifying genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Mutations in ARID1A represent one of the most common molecular alterations in human cancer, but therapeutic approaches that target these defects are not yet clinically available. We demonstrate that defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis. The data presented here provide the pre-clinical and mechanistic rationale for assessing ARID1A defects as a biomarker of single-agent ATR inhibitor response and represents a novel synthetic lethal approach to targeting tumour cells.

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