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A specific CBP/p300-dependent gene expression program drives the metabolic remodelling in late stages of spermatogenesis.

ABSTRACT: Histone hyperacetylation is thought to drive the replacement of histones by transition proteins that occurs in elongating spermatids after a general shut-down of transcription. The molecular machineries underlying this histone hyperacetylation remain still undefined. Here we focused our attention on the role of Cbp and p300 in histone hyperacetylation and in the preceding late gene transcriptional activity in elongating spermatids. A strategy was designed to partially deplete Cbp and p300 in elongating spermatids. These cells progressed normally through spermiogenesis and showed normal histone hyperacetylation and removal. However, a genome-wide transcriptomic analysis, performed in the round and elongating spermatids, revealed the existence of a gene regulatory circuit encompassing genes presenting high expression levels in pre-meiotic cells, undergoing a repressed state in spermatocytes and early post-meiotic cells, but becoming reactivated in elongating spermatids, just prior to the global shut-down of transcription. Interestingly, this group of genes was over-represented within the genes affected by Cbp/p300 knock-down and were all involved in metabolic remodelling. This study revealed the occurrence of a tightly regulated Cbp/p300-dependent gene expression program that drives a specific metabolic state both in progenitor spermatogenic cells and in late transcriptionally active spermatids and confirmed a special link between Cpb/p300 and cell metabolism programming previously shown in somatic cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE55767 | GEO | 2014/03/12

SECONDARY ACCESSION(S): PRJNA240962

REPOSITORIES: GEO

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A specific CBP/p300-dependent gene expression program drives the metabolic remodelling in late stages of spermatogenesis.

Project description:Histone hyperacetylation is thought to drive the replacement of histones by transition proteins that occurs in elongating spermatids after a general shut-down of transcription. The molecular machineries underlying this histone hyperacetylation remain still undefined. Here we focused our attention on the role of Cbp and p300 in histone hyperacetylation and in the preceding late gene transcriptional activity in elongating spermatids. A strategy was designed to partially deplete Cbp and p300 in elongating spermatids. These cells progressed normally through spermiogenesis and showed normal histone hyperacetylation and removal. However, a genome-wide transcriptomic analysis, performed in the round and elongating spermatids, revealed the existence of a gene regulatory circuit encompassing genes presenting high expression levels in pre-meiotic cells, undergoing a repressed state in spermatocytes and early post-meiotic cells, but becoming reactivated in elongating spermatids, just prior to the global shut-down of transcription. Interestingly, this group of genes was over-represented within the genes affected by Cbp/p300 knock-down and were all involved in metabolic remodelling. This study revealed the occurrence of a tightly regulated Cbp/p300-dependent gene expression program that drives a specific metabolic state both in progenitor spermatogenic cells and in late transcriptionally active spermatids and confirmed a special link between Cpb/p300 and cell metabolism programming previously shown in somatic cells. Total RNA were obtained from post meiotic male germ cells (round spermatids and condensing spermatids) of adult mice either wild-type or with a double knock down of Cbp/P300 in post-meiotic cells. In each experiments, 6 replicates of each genotype and cell type were used.

2014-03-12 | E-GEOD-55767 | biostudies-arrayexpress

Nut interactome in round/elongating spermatids

Project description:NUT, nuclear protein in testis is the universal fusion partner of BRD4 in the highly aggressive NUT Midline Carcinoma (NMC), but its physiological function was unknown. Here we show that Nut is exclusively expressed in post-meiotic spermatogenic cells, at the time of genome-wide histone hyperacetylation. Inactivation of Nut induces a spermatogenesis arrest at the histone-to-protamine replacement stage, leading to male infertility. Subsequent molecular investigations show that Nut sustains global histone H4 hyperacetylation in post-meiotic cells. Additionally, Nut mediates a p300/CBP-dependent gene expression program and, by enhancing acetylation of H4 at both K5 and K8 sites, provides binding sites for the first bromodomain of Brdt, which drives histone removal. Nut’s major function is therefore to use the ubiquitous HATs p300/CBP to direct a cell-type specific histone hyperacetylation. Its ectopic activity in NMC recreates a forced p300-induced histone hyperacetylation / bromodomain binding loop that normally operates in post-meiotic spermatogenic cells.

2018-10-02 | PXD008727 | Pride

Nut is a cell type-specific stimulator of p300 enhancing H4 hyperacetylation during haploid male genome programming

Project description:NUT, nuclear protein in testis is the universal fusion partner of BRD4 in the highly aggressive NUT Midline Carcinoma (NMC), but its physiological function is unknown. Here we show that Nut is exclusively expressed in post-meiotic spermatogenic cells, at the time of genome-wide histone hyperacetylation. Inactivation of Nut induces a spermatogenesis arrest at the histone-to-protamine replacement stage, leading to male infertility. Subsequent molecular investigations show that Nut sustains global histone H4 hyperacetylation in post-meiotic cells. Additionally, Nut mediates a p300/CBP-dependent gene expression program and, by enhancing acetylation of H4 at both K5 and K8 sites, provides binding sites for the first bromodomain of Brdt, which drives histone removal. Our results bring the first evidence of Nut’s function in spermatogenic cells where it uses the ubiquitous HATs p300/CBP to direct a cell-type specific histone H4 hyperacetylation. The ectopic activity of Nut in NMC recreates a forced p300-induced histone hyperacetylation / bromodomain-binding loop that normally operates in post-meiotic spermatogenic cells.

2018-10-15 | GSE111931 | GEO

Characterization of TP2 interactome

Project description:Spermiogenesis is marked by an almost genome-wide histone-to-protamine transition. Protamines are sperm-specific, small and highly positively charged proteins mainly responsible for genome compaction at this step. According to previous investigations from our lab and other groups, it is known that just before their removal, histones become hyperacetylated, which creates binding sites for the first bromodomain of a testis-specific member of the BET double bromodomain protein family, Brdt. Brdt’s first bromodomain is necessary for transition proteins (TPs) and PRMs incorporation and subsequent histone removal. Histone hyperacetylation, specifically on H4 lysine residues 5 and 8 which are recognized by Brdt, is controlled by a post-meiotic enhancer of CBP/p300 acetyltransferase activity, known as Nut. The process of TP assembly itself is dependent on a prior incorporation of a histone variant known as H2A.L.2, expressed in the same cells and at the same time as TPs. To characterize the proteins associating with TP2, we performed a mass spectrometry-based proteomics analysis of TP2 co-immunoprecipitations elutes from condensing spermatids extract. The immunoprecipitation was performed using extract from stages 12-16 spermatids from wild-type and H2A.L.2-KO mice. In parallel, immunopurifications were performed using a non-specific antibody (pre-immune goat serum) to allow the identification of proteins specifically purified with TP2 as opposed to proteins non-specifically precipitated.

2022-02-14 | PXD031665 | Pride

Nut directs p300-dependant genome-wide H4 hyperacetylation in male germ cells: transcriptomic data

Project description:NUT, nuclear protein in testis, is a universal oncogenic driver in the highly aggressive NUT Midline Carcinoma whose physiological function in male germ cells had so far remained unknown. Here we show that Nut’s expression is normally restricted to post-meiotic spermatogenic cells, where its presence triggers the p300-dependant genome-wide histone H4 hyperacetylation, which is essential for the completion of histone-to-protamine exchange. Accordingly, the inactivation of Nut induces male sterility with spermatogenesis arrest at the histone removal stage. Molecular investigations show that Nut uses CBP/p300 to enhance acetylation of H4 at both K5 and K8 providing binding sites for the first bromodomain of Brdt, the testis-specific member of the BET family, which subsequently mediates genome-wide histone removal. Altogether, our data reveal the detailed molecular basis of the global histone hyperacetylation wave, which has long been known to occur prior to the final compaction of the male genome.

2018-10-15 | GSE118969 | GEO

Epigenetic mechanisms to propagate histone acetylation by p300/CBP

Project description:Histone acetylation is important for the activation of gene transcription but little is known about its direct ‘read/write’ mechanisms. Here, we report cryo-electron microscopy structures in which a p300/CBP multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTac via the bromodomain pocket responsible for ‘reading’, but also interacted with the DNA minor grooves via the outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 ‘writes’ by ‘reading’ H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP ‘replicates’ histone NT acetylation within the H3-H4 tetramer to inherit epigenetic storage, and ‘transcribes’ it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.

2023-05-08 | PXD040835 | Pride

Time-resolved analysis reveals rapid dynamics and broad scope of the CBP/p300 acetylome

Project description:The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators; however, their acetylation targets, site-specific acetylation kinetics, and function in proteome regulation are incompletely understood. We combined quantitative proteomics with novel CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to show that CBP/p300 acetylates thousands of sites, including signature histone sites, as well as a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Kinetic analysis identified a subset of CBP/p300-regulated sites with very rapid (<30min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions, as well as for understanding the impact of small molecule inhibitors targeting its catalytic and bromodomain activities.

2018-06-10 | PXD005252 | Pride

The histone acetyl transferases CBP and p300 regulate stress response pathways in synovial fibroblasts

Project description:The activation of stress response pathways in synovial fibroblasts (SF) is a hallmark of rheumatoid arthritis (RA). CBP and p300 are two highly homologous histone acetyl transferases and writers of activating histone 3 lysine 27 acetylation (H3K27ac) marks. We investigated individual functions of CBP and p300 using a silencing strategy, followed by RNA-sequencing, and pathway enrichment analysis. We have selected stress-related pathways for a further in-depth investigation of individual functions of CBP and p300 in SF. Pathway enrichment analysis pointed to a profound role of CBP and/ or p300 in regulating stress response-related gene expression, with an enrichment of pathways associated with oxidative stress, hypoxia, autophagy and proteasome function. We silenced CBP or p300, and performed confirmatory experiments on transcriptome, protein and functional levels. We have identified some overlap of CBP and p300 target genes in the oxidative stress response pathway, however, with several genes being regulated in opposite directions. The majority of stress response genes was regulated by p300, with a specific function of p300 in regulating hypoxia response genes and genes encoding proteasome subunits. Silencing of p300 suppressed proteasome enzymatic activities. CBP and p300 regulated autophagy on transcriptome and functional levels. Whereas CBP was indispensable for autophagy synthesis, silencing of p300 affected late-stage autophagy. In line with impaired autophagy and proteasome function, poly-ubiquitinated proteins accumulated after silencing of p300.

2023-07-04 | GSE236122 | GEO

Time-resolved analysis reveals rapid dynamics and broad scope of the CBP/p300 acetylome

| MSV000095981 | MassIVE

Expression data from shMiwi/shCaf1 transduced mouse elongating spermatids

Project description:We reasoned that the pi-RISC, by virtue of the enormous sequence portfolio of piRNAs, might mediate elimination of a large variety of mRNAs in late stages of spermiogenesis. Both Miwi-null and Caf1-null mice showed early spermiogenic arrest, preventing us from determining the role of MIWI and CAF1 in elongating spermatids using the existing genetic models. We therefore used microarrays to detail the global effect of MIWI or CAF1 on mRNA levels in mouse elongating spermatids. Using GFP+ elongating spermatids sorted from mouse testes transduced with shMiwi:GFP, shCaf1:GFP, or control pSilencer:GFP, we performed transcriptome profiling on Affymetrix mouse arrays.

2014-07-11 | E-GEOD-59291 | biostudies-arrayexpress

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