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BRD4 dynamics reveal novel acrosome-dependent chromatin reorganization during post-meiotic mammalian sperm development

ABSTRACT: During the post-meiotic phase of spermatogenesis, transcription is progressively repressed as the nuclei of haploid spermatids are compacted through a dramatic chromatin reorganization involving hyper-acetylation and replacement of most histones with sperm-specific protamines. Although BRDT has been shown to function in transcription as well as histone removal in post-meiotic spermatids, it is unknown whether other BET family proteins play a role. Immunofluorescence of mouse testes revealed BRD4 in a complete ring around the nuclei of spermatids containing hyper-acetylated histones. The BRD4 ring lies directly adjacent to the acroplaxome, or the cytoskeletal base of the acrosome, and does not form in acrosomal mutant mice. ChIP sequencing in round spermatids revealed enrichment of BRD4 and acetylated histone H3 and H4 at the promoters of active genes. GO Term analysis showed that BRD4 and BRDT bind to distinct subsets of spermatogenesis-specific genes. Association of BRD4 with Cyclin T1 decreases as spermatogenesis progresses despite a persistence of association with acetylated H4. Moreover, acetylated histones are removed from the condensing spermatid nucleus in a wave following the progressing acrosome. These data provide evidence for an interesting mechanism in which BRD4 and perhaps acetylated histones are removed from the spermatid genome via the progressing acrosome as transcription is repressed.

ORGANISM(S): Mus musculus

PROVIDER: GSE56526 | GEO | 2015/03/06

SECONDARY ACCESSION(S): PRJNA243627

REPOSITORIES: GEO

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BRD4 dynamics reveal novel acrosome-dependent chromatin reorganization during post-meiotic mammalian sperm development

Project description:During the post-meiotic phase of spermatogenesis, transcription is progressively repressed as the nuclei of haploid spermatids are compacted through a dramatic chromatin reorganization involving hyper-acetylation and replacement of most histones with sperm-specific protamines. Although BRDT has been shown to function in transcription as well as histone removal in post-meiotic spermatids, it is unknown whether other BET family proteins play a role. Immunofluorescence of mouse testes revealed BRD4 in a complete ring around the nuclei of spermatids containing hyper-acetylated histones. The BRD4 ring lies directly adjacent to the acroplaxome, or the cytoskeletal base of the acrosome, and does not form in acrosomal mutant mice. ChIP sequencing in round spermatids revealed enrichment of BRD4 and acetylated histone H3 and H4 at the promoters of active genes. GO Term analysis showed that BRD4 and BRDT bind to distinct subsets of spermatogenesis-specific genes. Association of BRD4 with Cyclin T1 decreases as spermatogenesis progresses despite a persistence of association with acetylated H4. Moreover, acetylated histones are removed from the condensing spermatid nucleus in a wave following the progressing acrosome. These data provide evidence for an interesting mechanism in which BRD4 and perhaps acetylated histones are removed from the spermatid genome via the progressing acrosome as transcription is repressed. Single replicates each of Brd4, H3K9me3, H3K9ac, H4K5ac, H4K8ac, H4K12ac, H4K16ac, H4Kac (pan-acetyl antibody), and input in mouse round spermatid cells; input is used to control for local sonication efficiency bias.

2015-03-06 | E-GEOD-56526 | biostudies-arrayexpress

Genome-wide analysis of the distribution of the testis-specific double bromodomain protein BRDT reveals distinct roles in pachytene spermatocyte and round spermatids

Project description:BRDT, a member of the BET family of double bromodomain-containing proteins, is expressed uniquely in the testis from pachytene spermatocytes through round spermatids, and is essential for spermatogenesis in the mouse. Although BRDT is known to bind to acetylated lysines in chromatin, it is not known where in the genome BRDT binds or whether the sites vary during the complex stages of differentiation in which it is expressed. Herein, we use ChIP-Seq to identify genome-wide BRDT binding sites in chromatin from mouse male germ cells at two distinct stages of differentiation. We identified 5452 BRDT-bound genomic loci in pachytene spermatocytes and 5618 BRDT-bound genomic loci in round spermatids. Roughly two thirds of BRDT binding sites were located in genes and BRDT binding correlated with highly transcribed genes. BRDT binding sites also overlapped with several histone modifications or variants that are associated with active transcription. Motif analysis revealed that BRDT-bound regions are enriched for consensus sequences for the MYB, RFX, ETS and ELF1 in pachytene spermatocytes, and JunD, c-Jun, CRE and RFX in round spermatids. Taken together, our data suggest that BRDT regulates distinct downstream target genes and may have unique functions in the meiotic and spermiogenic transcription programs.

2021-01-26 | GSE98489 | GEO

PHF7 Modulates BRDT Stability and Histone-to-Protamine Exchange during Spermiogenesis

Project description:Spermatogenesis is a complex process of sperm generation, including mitosis, meiosis, and spermiogenesis. During spermiogenesis, histones in post-meiotic spermatids are removed from chromatin and replaced by protamines. Although histone-to-protamine exchange is important for sperm nuclear condensation, the underlying regulatory mechanism is still poorly understood. Here, we identify PHD finger protein 7 (PHF7) as an E3 ubiquitin ligase for histone H3K14 in post-meiotic spermatids. Generation of Phf7-deficient mice and Phf7 C160A knockin mice with impaired E3 ubiquitin ligase activity reveals defects in histone-to-protamine exchange caused by dysregulation of histone removal factor Bromodomain, testis-specific (BRDT) in early condensing spermatids. Surprisingly, E3 ubiquitin ligase activity of PHF7 on histone ubiquitination leads to stabilization of BRDT by attenuating ubiquitination of BRDT. Collectively, our findings identify PHF7 as a critical factor for sperm chromatin condensation and contribute to mechanistic understanding of fundamental phenomenon of histone-to-protamine exchange and potential for drug development for the male reproduction system.

2020-07-28 | GSE136752 | GEO

Bromodomain-dependent stage-specific male genome programming by Brdt [ChIP-Seq]

Project description:Male germ cell differentiation is a highly regulated multistep process initiated by the commitment of progenitor cells into meiosis and characterized by major chromatin reorganizations in haploid spermatids. We report here that a single member of the double bromodomain BET factors, Brdt, is a master regulator of both meiotic divisions and post-meiotic genome repackaging. Upon its activation at the onset of meiosis, Brdt drives and determines the developmental timing of a testis-specific gene expression program. In meiotic cells, Brdt initiates a genuine histone acetylation-guided programming of the genome by activating essential meiotic genes and repressing a M-bM-^@M-^\progenitor cellsM-bM-^@M-^] gene expression program, while M-bM-^@M-^\primingM-bM-^@M-^] a post-meiotic gene group for further activation. At post-meiotic stages, a global chromatin hyperacetylation gives the signal for BrdtM-bM-^@M-^Ys first bromodomain to direct the genome-wide replacement of histones by transition proteins. Brdt is therefore a unique and essential regulator of male germ cell differentiation, which, by using various domains in a developmentally controlled manner, first drives a specific spermatogenic gene expression program, and later controls the tight packaging of the male genome. Examination of Brdt binding on chromatin in meiotic (spermatocytes) and post-meiotic (round spermatids) male germ cells from adult wild type mice

2012-08-30 | E-GEOD-39908 | biostudies-arrayexpress

Tsga8 is required for spermatid morphogenesis and male fertility in mice

Project description:During spermatogenesis, intricate gene expression is coordinately regulated by epigenetic modifiers, which are required for differentiation of spermatogonial stem cells (SSCs) contained among undifferentiated spermatogonia. We previously found that KMT2B conveys H3K4me3 at bivalent and monovalent promoters in undifferentiated spermatogonia. Because these genes are expressed late in spermatogenesis or during embryogenesis, we expect that many of them are potentially programmed by KMT2B for future expression. Here, we show that one of the genes targeted by KMT2B, Tsga8, plays an essential role in spermatid morphogenesis. Loss of Tsga8 in mice leads to male infertility associated with abnormal chromosomal distribution in round spermatids, malformation of elongating spermatid heads and spermiation failure. Tsga8 depletion leads to dysregulation of thousands of genes, including the X chromosome genes that are reactivated in spermatids, and insufficient nuclear condensation accompanied by reductions of TNP1 and PRM1, key factors for histone-to-protamine transition. Intracytoplasmic sperm injection (ICSI) of spermatids rescued the infertility phenotype, suggesting competency of the spermatid genome for fertilization. Thus, Tsga8 is a KMT2B target that is vitally necessary for spermiogenesis and fertility.

2021-04-16 | GSE147805 | GEO

Expression data from purified control and BrdtΔBD1 round spermatids.

Project description:Brdt is a testis specific member of a family of chromatin interacting proteins. All of the family members have been shown to regulate transcription. Brdt is highly expressed in round spermatids, and may play a role in transcriptional regulation in these cells. We investigated transcriptional changes in mutant round spermatids that were homozygous for a mutation in which the first bromodomain of Brdt was removed. Round spermatids were purified from seven adult animals of each genotype for each Affymetrix microarray. Purity of round spermatids was assessed by propidium iodide staining.

2011-10-20 | E-GEOD-33132 | biostudies-arrayexpress

Bromodomain-dependent stage-specific male genome programming by Brdt [Illumina BeadArray]

Project description:Male germ cell differentiation is a highly regulated multistep process initiated by the commitment of progenitor cells into meiosis and characterized by major chromatin reorganizations in haploid spermatids. We report here that a single member of the double bromodomain BET factors, Brdt, is a master regulator of both meiotic divisions and post-meiotic genome repackaging. Upon its activation at the onset of meiosis, Brdt drives and determines the developmental timing of a testis-specific gene expression program. In meiotic cells, Brdt initiates a genuine histone acetylation-guided programming of the genome by activating essential meiotic genes and repressing a “progenitor cells” gene expression program, while “priming” a post-meiotic gene group for further activation. At post-meiotic stages, a global chromatin hyperacetylation gives the signal for Brdt’s first bromodomain to direct the genome-wide replacement of histones by transition proteins. Brdt is therefore a unique and essential regulator of male germ cell differentiation, which, by using various domains in a developmentally controlled manner, first drives a specific spermatogenic gene expression program, and later controls the tight packaging of the male genome. Total RNA obtained from testes from prepuberal mice at 17dpp and at 20dpp were compared between Brdt-/- and Brdt+/- (17dpp), between Brdt-/- and Brdt +/+ (20dpp) and between BrdtBD1del and Brdt wt mice (20dpp). In each experiments, 6 replicates of each genotype and condition were used.

2012-08-30 | E-GEOD-39909 | biostudies-arrayexpress

ClpP-deletion causes azoospermia, with meiosis-I delay and insufficient biosynthesis of spermatid factors, due to mitochondrial dysfunction with accumulation of Perrault proteins ERAL1, PEO1, and HARS2.

Project description:Human Perrault syndrome (PRLTS) is defined by autosomal recessive inheritance with primary ovarian insufficiency and early hearing loss. Most PRLTS disease proteins modulate mitochondrial transcription or translation. Among the genetic causes are ClpP mutations, which trigger also complete azoospermia, whose cellular and molecular underpinnings are unknown. Here, the ClpP-null mouse model was studied by global transcriptomics, proteomics, RT-qPCR, immunoblots, tissue fractionation, testis histology, and was crossed with STING/IFNAR mutants. Spermatogenesis showed accumulated early spermatocytes, versus deficits of desynapsis and kinetochore factors; excess Dazl/Stra8 and acetylSMC3, versus deficient SHCBP1L, were molecular correlates. Spermiogenesis showed few round spermatids, tsHMG/TFAM in elongated spermatids was absent; transcripts for tail/acrosome factors were downregulated from start. Nuclear anomalies included a failed Rec8 induction, early BRDT deficiency, histone H3 cleavage, and cGAMP increase, as antiviral responses typical of ClpP-mutants. However, deletion of downstream innate immune signals STING/IFNAR failed to reestablish fertility. As mitochondrial triggers, we observed accumulation of ClpX, with PTCD1, POLDIP2, GRSF1, ALKBH7, DNAJA3, AURKAIP1, VWA8, and Perrault proteins ERAL1, PEO1, HARS2, partially showing nuclear redistribution. ClpP-depletion is known to cause extra-mitochondrial release of mispacked mtDNA/mtRNA/protein complexes. Now we define nuclear inflammatory responses and meiotic arrest as consequences, similar to observations in mito-mice and mutator mice.

2023-03-11 | PXD033388 | Pride

Expression data from purified control and BrdtΔBD1 round spermatids.

2011-10-21 | GSE33132 | GEO

DOT1L regulates chromatin reorganization and gene expression during sperm differentiation

Project description:Spermatozoa have a unique genome organization: their chromatin is almost completely devoid of histones and is formed instead of protamines which confer a high level of compaction and preserve paternal genome integrity until fertilization. Histone-to-protamine transition takes place in spermatids and is indispensable for the production of functional sperm. Here we show that the H3K79-methyltransferase DOT1L controls spermatid chromatin remodelling and subsequent reorganization and compaction of spermatozoon genome. Using a mouse model in which Dot1l is knocked-out (KO) in postnatal male germ cells, we found that Dot1l-KO sperm chromatin is less compact and has an abnormal content, characterized by the presence of transition proteins, immature protamine 2 forms and a higher level of histones. Proteomics and transcriptomics analyses performed on spermatids reveal that Dot1l-KO modifies the chromatin prior to histone removal, and leads to the deregulation of genes involved in flagellum formation and apoptosis during spermatid differentiation. As a consequence of these chromatin and gene expression defects, Dot1l-KO spermatozoa have less compact heads and are less motile, which results in impaired fertility.

2023-03-30 | PXD030734 | Pride

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