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SRCAP Mutations Drive Clonal Hematopoiesis Through Epigenetic and DNA Repair Dysregulation [Cut & Run]

ABSTRACT: To investigate how Srcap mutations confer mutant hematopoietic stem and progenitor cells (HSPCs) with selective advantage after transplantation We assessed SRCAP chromatin remodeling and corresponding H2A.Z incorporation using Cut-and-run sequencing

ORGANISM(S): Mus musculus

PROVIDER: GSE229864 | GEO | 2023/10/19

REPOSITORIES: GEO

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SRCAP Mutations Drive Clonal Hematopoiesis Through Epigenetic and DNA Repair Dysregulation [ATAC-Seq]

Project description:To investigate how Srcap mutations confer mutant hematopoietic stem and progenitor cells (HSPCs) with selective advantage after transplantation We assessed chromatin remodeling and chromatin accessbility before and after transplantation to understand the mechanism of the acquisition of Srcap selective advantage

2023-10-19 | GSE229862 | GEO

SRCAP Mutations Drive Clonal Hematopoiesis Through Epigenetic and DNA Repair Dysregulation [RNA-seq]

Project description:To investigate how Srcap mutations confer mutant hematopoietic stem and progenitor cells (HSPCs) with selective advantage after exposure to cellular stressors, transplantation and doxorubicin treatment We established Srcap heterozygous mutant murine model and utilized competitive bone marrow transplantation to assess the transcriptome of donor cells using RNA-seq

2023-10-19 | GSE229865 | GEO

SRCAP Mutations Drive Clonal Hematopoiesis Through Epigenetic and DNA Repair Dysregulation [scRNA-Seq]

Project description:To investigate the transcriptomic regulation of Srcap mutant lymphoid-biased expansion after compeititve transplantation

2023-10-19 | GSE230153 | GEO

Structural insights into histone exchange by human SRCAP complex

Project description:Histone variant H2A.Z is found at promoters and regulates transcription. The ATP-dependent chromatin remodeler SRCAP complex (SRCAP-C) promotes the replacement of canonical histone H2A-H2B dimer with H2A.Z-H2B dimer. Here, we determined structures of human SRCAP-C bound to H2A-containing nucleosome at near-atomic resolution. The SRCAP subunit integrates a 6-subunit actin-related protein (ARP) module and an ATPase-containing motor module. The ATPase-associated ARP module encircles half of the nucleosome along the DNA and may restrain net DNA translocation, a unique feature of SRCAP-C. The motor module adopts distinct nucleosome-binding modes in the apo (nucleotide-free), ADP-bound, and ADP-BeFx-bound states, suggesting that ATPase-driven movement destabilizes H2A-H2B by unwrapping the entry DNA and pulls H2A-H2B out of nucleosome through the ZNHIT1 subunit. Structure-guided chromatin immunoprecipitation (ChIP) sequencing analysis confirmed the requirement of H2A-contacting ZNHIT1 in maintaining H2A.Z occupancy on the genome. Our study provides structural insights into the mechanism of H2A-H2A.Z exchange mediated by SRCAP-C.

2024-02-10 | GSE249825 | GEO

SRCAP Mutations Drive Clonal Hematopoiesis Through Epigenetic and DNA Repair Dysregulation

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-10-19 | GSE230155 | GEO

Single amino acid change underlies distinct roles of H2A.Z subtypes in human syndrome

Project description:Craniofacial disorder Floating-Harbor Syndrome (FHS) is caused by heterozygous truncating mutations in SRCAP, a gene encoding a chromatin remodeler mediating incorporation of histone variant H2A.Z. Here, we demonstrate that FHS-associated mutations result in loss of SRCAP nuclear localization, alter neural crest gene programs in human in vitro models and Xenopus embryos, and cause craniofacial defects. These defects are mediated by one of two H2A.Z subtypes, H2A.Z.2, whose knockdown mimics and whose overexpression rescues the FHS phenotype. Selective rescue by H2A.Z.2 is conferred by one of the three amino acid differences between the H2A.Z subtypes, S38/T38. We further show that H2A.Z.1 and H2A.Z.2 genomic occupancy patterns are qualitatively similar, but quantitatively distinct, and that H2A.Z.2 incorporation at AT-rich enhancers and expression of their associated genes are both sensitized to SRCAP truncations. Altogether, our results illuminate the mechanism underlying a human syndrome and uncover selective functions of H2A.Z subtypes during development.

2019-09-11 | GSE134532 | GEO

CUT&Tag for H2A.Z using mouse heart tissues from control and Znhit1-deficient mice

Project description:Znhit1 is an important subunit of the SRCAP complex, which regulates gene transcription by replacing histone H2A with a variant H2A.Z at gene promoter regions. Deletion of Znhit1 has also been reported to impact the incorporation of H2A.Z in genome. To explore the function of Znhit1 in heart tissues, we performed CUT&Tag assays for H2A.Z to examine the distribution changes of H2A.Z on the genome.

2022-04-19 | GSE194162 | GEO

SRCAP ChIP-sequencing of mouse intestinal stem cells (ISCs)

Project description:We previously demonstrated that SRCAP regulates the self-renewal of ESCs and modulates lymphoid lineage commitment. We further validated that SRCAP was mainly distributed in liver, spleen and intestine by Northern blot. SRCAP was also highly expressed in Lgr5+ ISCs. We then sought to explore the physiological role of SRCAP in the regulation of self-renewal maintenance of ISCs.We identified that Srcap deficiency impairs the self-renewal of ISCs and intestinal epithelial regeneration. Through SRCAP ChIP-sequencing, we sough to identify the key gene regulated by SRCAP in ISC self-renewal.

2020-01-28 | GSE144267 | GEO

Coordinated Chromatin Remodeling induced by Demethylation requires SRCAP mediated H2A.Z exchange

Project description:Coordinated Chromatin Remodeling induced by Demethylation requires SRCAP mediated H2A.Z exchange

| PRJNA136591 | ENA

H2A.Z chaperones promote melanoma cell growth by facilitating transcription of E2F target genes through H2A.Z deposition and H4 acetylation

Project description:High levels of the histone variant H2A.Z are characteristic for melanoma progression and correlate with poor prognosis of melanoma patients. Two chaperone complexes are reported to deposit H2A.Z isoforms into chromatin: SRCAP and P400-TIP60. YL1 is a common subunit of both complexes and directly binds to the H2A.Z-H2B dimer. Here, we showed that the knockdown of SRCAP (SRCAP-specific), P400 (P400-TIP60-specific) and YL1 (shared subunit) results in loss of H2A.Z deposition into chromatin in melanoma cells, confirming them as H2A.Z chaperone subunits in this system. Further, we demonstrated that H2A.Z, YL1 and the SRCAP-specific subunit ZNHIT1 co-localize at active promoters of cell cycle-related genes, such as the transcription factor E2F1. Knockdown of YL1, SRCAP and P400 downregulates E2F1 and its targets, resulting in a loss of proliferation and cell cycle arrest in melanoma cells as seen after knockdown of H2A.Z (Vardabasso et al. 2015). Strikingly, besides H2A.Z loss, we observed a dramatic loss of H4 acetylation in melanoma chromatin upon knockdown of H2A.Z chaperone subunits. The majority of genes whose promoters showed a reduction in H4 acetylation were previously bound by H2A.Z, YL1 and ZNHIT1. This is suggestive of a direct link between H2A.Z deposition and H4 acetylation to promote the expression of underlying genes. In agreement, the genes that lost H4 acetylation were enriched for E2F1 target genes. Interestingly, we additionally found that knockdown of YL1 did not only prohibit cell cycle progression, but also induces apoptosis, which is in contrast to H2A.Z knockdown affecting cell cycle only. In addition, YL1 (but not SRCAP or P400) was found to be overexpressed in melanoma and high YL1 levels were a predictor of poor melanoma patient outcome. These findings provide a rationale for targeting the H2A.Z-YL1 interaction as novel epigenetic strategy for melanoma treatment.

2024-05-10 | GSE242227 | GEO

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