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SRCAP mutation promotes cutatneous squamous cell carcinoma invasion [RNA-Seq]

ABSTRACT: In this study, we identify a mutational hotspot affecting SRCAP in cancer and that SRCAP is recurrently mutated in keratinocyte carcinomas. When introduced to primary human epidermal keratinocytes, the SRCAP hotspot mutation dysregulates gene expression in the differentiated state far more than the progenitor state. Gene dysregulation occurs without a change in H2A.Z chromatin occupancy. Finall, the presence of the SRCAP mutation in a RAS-CDK4 driven model of cSCC increases invasion significantly.

ORGANISM(S): Homo sapiens

PROVIDER: GSE292168 | GEO | 2025/08/01

REPOSITORIES: GEO

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SRCAP mutation promotes cutatneous squamous cell carcinoma invasion [ChIP-Seq]

Project description:In this study, we identify a mutational hotspot affecting SRCAP in cancer and that SRCAP is recurrently mutated in keratinocyte carcinomas. When introduced to primary human epidermal keratinocytes, the SRCAP hotspot mutation dysregulates gene expression in the differentiated state far more than the progenitor state. Gene dysregulation occurs without a change in H2A.Z chromatin occupancy. Finall, the presence of the SRCAP mutation in a RAS-CDK4 driven model of cSCC increases invasion significantly.

2025-08-01 | GSE292167 | 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.

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

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Growth signaling promotes H2A.Z deposition by SRCAP to sustain somatic tissue regeneration [ChIP-Seq]

Project description:In this study, we find that H2A.Z expression and chromatin occupancy dramatically decrease during normal epidermal differentiation. While the chromatin remodeler SRCAP is necessary and sufficient to maintain H2A.Z deposition in epidermal progenitors, EP400 is dispensable. Growth factor signaling mediated by the MAPK and PI3K signaling pathways is necessary to maintain both the expression and deposition of H2A.Z. Loss of SRCAP, H2AZ1, or H2AZ2 induces nuclear deformation and cytoplasmic DNA in progenitor keratinocytes which impairs DNA repair and proliferation.

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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.

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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

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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.

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

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SRCAP mutation promotes cutatneous squamous cell carcinoma invasion [RNA-Seq]

Project description:SRCAP mutation promotes cutatneous squamous cell carcinoma invasion [RNA-Seq]

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