Growth signaling promotes H2A.Z deposition by SRCAP to sustain somatic tissue regeneration [RNA-Seq]
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PROVIDER: PRJNA1168139 | ENA |
REPOSITORIES: ENA
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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.
2025-08-01 | GSE278642 | GEO
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.
2025-08-01 | GSE278641 | GEO
Project description:Growth signaling promotes H2A.Z deposition by SRCAP to sustain somatic tissue regeneration [ChIP-Seq]
| PRJNA1168137 | ENA
Project description:DNA methylation and the histone variant H2A.Z are maintained in mutually exclusive sections of the genome. How this antagonism is established, however, remains an open question. Here, we examined the impacts of DNA methylation on both the intrinsic stability of H2A.Z nucleosomes and chaperone-mediated H2A.Z deposition. Cryo-EM and endonuclease-based assays show that H2A.Z nucleosomes on methylated DNA substrates are more open and accessible compared to their unmethylated counterparts. In Xenopus, H2A.Z preferentially associates with unmethylated DNA of both sperm pronuclei in the transcriptionally silent egg extract as well as in somatic cells, though a substantial proportion of H2A.Z colocalizes with DNA methylation in sperm pronuclei. By monitoring nucleosome assembly on synthetic DNA constructs in egg extract, we find that the H2A.Z bias for unmethylated substrates is dependent on the SRCAP complex. Accordingly, DNA-binding of SRCAP is suppressed by DNA methylation. Altogether, we propose that the SRCAP complex is the major determinant for preferential H2A.Z enrichment on unmethylated DNA, and that DNA methylation destabilizes DNA wrapping in H2A.Z-containing nucleosomes.
2025-10-28 | GSE295057 | GEO
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
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 | GSE246121 | GEO
Project description:The histone variant H2A.Z is essential for maintaining the identity of embryonic stem cell (ESC) by keeping bivalent developmental genes at a poised state. However, how H2A.Z is deposited into the bivalent domains remains unknown. In mammals, two chromatin-remodeling complexes, Tip60/p400 and SRCAP, exchange the canonical histone H2A for H2A.Z in the chromatin. Here we show that Glioma Amplified Sequence 41 (Gas41), a shared subunit of the two H2A.Z-depositing complexes, functions as a reader of histone acetylation and recruits Tip60/p400 and SRCAP to deposit H2A.Z into specific chromatin regions including bivalent domains. The YEATS domain of Gas41 bound to acetylation on histone H3K27 and H3K14 both in vitro and in cells. Crystal structure of the Gas41 YEATS domain in complex with the H3K27ac peptide revealed that, similar to the AF9 and ENL YEATS domains, Gas41 YEATS forms a serine-lined aromatic cage for Kac recognition; mutations of either the aromatic residues of YEATS domain or the nearby residue of H3K27 abrogated the interaction. In mESCs, knockdown of Gas41 led to cell differentiation as the result of derepression of differentiation genes. Importantly, the differentiated morphology was rescued by expressing wild type Gas41, but not the YEATS domain mutated counterparts that do not recognize histone acetylation. Mechanically, we found that Gas41 depletion led to reduction of H2A.Z levels and a concomitant reduction of H3K27me3 levels at the promoters of a subset of bivalent genes. Together, our study identifies the Gas41 YEATS domain as a reader of histone acetylation and establishes a link between histone acetylation and H2A.Z deposition in the maintenance of ESC identity.
2018-07-01 | GSE100460 | GEO
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
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 | GSE292168 | GEO
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