Tip60 complex promotes expression of a differentiation factor to regulate germline differentiation in female Drosophila
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ABSTRACT:
PROVIDER: PRJNA488790 | ENA |
REPOSITORIES: ENA
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Project description:Germline stem cells (GSCs) self-renew and differentiate to sustain a continuous production of gametes. In the female Drosophila germ line, two differentiation factors, bag of marbles (bam) and benign gonial cell neoplasm (bgcn), work in concert in the stem cell daughter to promote the generation of eggs. In GSCs, bam transcription is repressed by signaling from the niche and is activated in stem cell daughters. In contrast, bgcn is transcribed in both the GSCs and stem cell daughters, but little is known about how bgcn is transcriptionally modulated. Here, we find that the conserved protein Nipped_A acts through the Tat interactive protein 60kDa (Tip60) Histone acetyl transferase (HAT) complex in the germ line to promote GSC differentiation. We find that Nipped_A is required for efficient exit from the gap phase 2 (G2) of cell cycle of the GSC daughter and for expression of differentiation factor bgcn. Loss of Nipped_A results in accumulation of GSC daughters. Forced expression of bgcn, in Nipped_A germline-depleted ovaries rescues this differentiation defect. Together, our results indicate that Tip60 complex coordinates cell cycle progression and expression of bgcn to help drive GSC daughters toward a differentiation program.
2018-09-01 | GSE119328 | GEO
Project description: Not available
| S-EPMC6329907 | biostudies-literature
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
Project description:Stem cells establish cortical polarity and divide asymmetrically to simultaneously maintain themselves and generate differentiating offspring cells. Several chromatin modifiers have been identified as stemness factors in mammalian pluripotent stem cells, but whether these factors control stem cell polarity and asymmetric division has not been investigated so far. We addressed this question in Drosophila neural stem cells called neuroblasts. We identified the Tip60 chromatin remodeling complex and its interaction partner Myc to regulate target genes required for neuroblast maintenance. Knockdown of members of this complex results in loss of cortical polarity, symmetric neuroblast division and premature differentiation through nuclear entry of the transcription factor Prospero. We found that aPKC is the key target gene of Myc and the Tip60 complex subunit Domino regulating neuroblast polarity. Our transcriptome analysis further showed that Domino regulates the expression of mitotic spindle genes which were identified before as direct Myc targets. Our findings reveal an evolutionarily conserved functional link between Myc, the Tip60 complex and the molecular network controlling cell polarity and asymmetric cell division.
2018-07-06 | PXD009939 | Pride
Project description:The Tip60 (also known as Kat5) lysine acetyltransferase functions broadly as a transcriptional co-activator that acetylates histones. In contrast, Tip60 functions in embryonic stem cells (ESCs) both to silence genes that promote differentiation and to activate genes required for proliferation. The mechanism by which Tip60 functions as a repressor is unknown. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs and is necessary for complete silencing of most differentiation genes targeted by Tip60. In contrast to differentiated cells, where Hdac6 is mainly cytoplasmic and does not interact with Tip60, Hdac6 is largely nuclear in ESCs and neural stem cells (NSCs) and interacts with Tip60-p400 in both cell types. Hdac6 is enriched at promoters bound by Tip60-p400 in ESCs, but while Tip60 binds on both sides of transcription start sites (TSSs), Hdac6 binding overlaps with only the downstream Tip60 peak. Surprisingly, Hdac6 does not deacetylate histones at these sites, but rather is required for Tip60 binding. These data suggest that nuclear exclusion of Hdac6 during differentiation plays a major role in modulation of Tip60-p400 function. We determined the genome-wide localization of Tip60 and Hdac6 in mouse ES cells, and examined genomic binding profiles of Tip60 and Hdac6 upon indicated knockdown by ChIP-seq. We examined genomic binding profiles of p400 upon indicated knockdown by ChIP-seq.
2013-11-20 | E-GEOD-42209 | biostudies-arrayexpress
Project description:Female germline differentiation trajectory revealed by scRNA-seq
| PRJEB47244 | ENA
Project description:The Tip60 (also known as Kat5) lysine acetyltransferase functions broadly as a transcriptional co-activator that acetylates histones. In contrast, Tip60 functions in embryonic stem cells (ESCs) both to silence genes that promote differentiation and to activate genes required for proliferation. The mechanism by which Tip60 functions as a repressor is unknown. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs and is necessary for complete silencing of most differentiation genes targeted by Tip60. In contrast to differentiated cells, where Hdac6 is mainly cytoplasmic and does not interact with Tip60, Hdac6 is largely nuclear in ESCs and neural stem cells (NSCs) and interacts with Tip60-p400 in both cell types. Hdac6 is enriched at promoters bound by Tip60-p400 in ESCs, but while Tip60 binds on both sides of transcription start sites (TSSs), Hdac6 binding overlaps with only the downstream Tip60 peak. Surprisingly, Hdac6 does not deacetylate histones at these sites, but rather is required for Tip60 binding. These data suggest that nuclear exclusion of Hdac6 during differentiation plays a major role in modulation of Tip60-p400 function.
2013-11-20 | GSE42209 | GEO
Project description:Alternative splicing of RNA transcripts can result in a multitude of variations from the genome. Since splicing can occur co-transcriptionally, chromatin structure has been reported to affect the choice of a splice site. TIP60 is a haploinsufficient tumor suppressor gene that is frequently downregulated in cancers. Since TIP60 is a writer of histone and non-histone modifications, we investigated TIP60’s role in modulating alternative splicing. RNA sequencing was performed in TIP60-depleted MCF10A cells and with cells rescued with wild-type or catalytically inactive TIP60. The majority of the differential splicing events were skipped exon events, including exon 25 skipping event of ITGA6. To identify the splicing factor that regulates this event, a siRNA screen of 77 splicing factors was employed. TIP60 depletion results in an increase in the ITGA6 isoform that lacks exon 25 and the siRNA screen identified ESRP2 to regulate splicing of ITGA6 exon 25. This study suggests that alternative splicing of ITGA6 exon 25 is regulated by the TIP60-ESRP2 axis.
2023-06-19 | GSE152863 | GEO
Project description:A recurrent chromosomal translocation detected in cannibalistic acute myeloid leukemia leads to the production of a ZMYND11-MBTD1 fusion protein.
- The ZMYND11-MBTD1 fusion protein is stably incorporated into the endogenous NuA4/TIP60 complex
- ZMYND11-MBTD1 leads to mistargeting of NuA4-TIP60 activity to the coding region of ZMYND11-target genes, altering gene expression and transcript isoforms.
- ZMYND11-MBTD1 binds the MYC gene leading to its upregulation, favoring growth and pluripotency while inhibiting differentiation markers.
2021-04-17 | MSV000087226 | MassIVE