Tip60-mediated H2A.Z acetylation promotes neuronal fate specification and bivalent gene activation.
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ABSTRACT:
PROVIDER: PRJNA754094 | ENA |
REPOSITORIES: ENA
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Project description:Tip60-mediated H2A.Z acetylation is required for neuronal fate specification and bivalent gene activation [ATAC-Seq]
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Project description:Tip60-mediated H2A.Z acetylation is required for neuronal fate specification and bivalent gene activation [Cut & Tag]
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Project description:Tip60-mediated H2A.Z acetylation is required for neuronal fate specification and bivalent gene activation [RNA-Seq]
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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:Tip60-dependnet histone modification/occupancy dynamics during Ascl1-mediated direct reprogramming of mouse embryonic fibroblasts (MEFs) into induced neuronal cells.
2022-11-22 | GSE181888 | GEO
Project description:Examination of the effects of Tip60/Kat5 depletion on chromatin accessibility dynamics during Ascl1-mediated direct reprogramming of mouse embryonic fibroblasts (MEFs) into induced neuronal cells.
2022-11-22 | GSE181964 | GEO
Project description:Examination of the effects of Tip60/Kat5 depletion on gene expression dynamics during Ascl1-mediated direct reprogramming of mouse embryonic fibroblasts (MEFs) into induced neuronal cells.
2022-11-22 | GSE181887 | 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: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:Genome-wide mapping of TIP60 complex subunits in K562 cells. The objectives of this study are to describe TIP60 genome wide localization, confirm MBTD1 co-localization with already known unique subunits and observe the impact of MBTD1 on TIP60 complex targeting to chromatin. The TIP60 acetyltransferase complex is a key regulator of genome expression and stability. Here, we identified MBTD1 as a new stable subunit of the complex and revealed interesting insights about TIP60 function during the repair of DNA double strand breaks. MBTD1 binds H4K20me1/2, helping TIP60 association to specific promoters but also the DNA repair process by homologous recombination. While pro-end joining factor 53BP1 engages chromatin through simultaneous binding of H4K20me2 and H2AK15ub, TIP60 regulates the resolution of 53BP1 foci after DNA damage through a related bivalent mechanism. MBTD1 competes with 53BP1 for the H4K20me2 mark, affecting its retention at the break cooperatively with H4 acetylation by TIP60. In addition, we show that H2AK15ub deposition by RNF168 inhibits chromatin acetylation by TIP60, whereas H2AK15 can also be acetylated by TIP60 in vivo, therefore blocking its ubiquitylation. Altogether, these results uncover an intricate mechanism orchestrated by the TIP60 complex to regulate 53BP1-dependent repair pathway selection, through incompatible bivalent binding/action on chromatin.
2016-04-30 | GSE69645 | GEO