Active DNA damage response signaling initiates and maintains meiotic sex chromosome inactivation
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ABSTRACT:
PROVIDER: PRJNA870643 | ENA |
REPOSITORIES: ENA
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Project description:Meiotic sex chromosome inactivation (MSCI) is an essential process in the male germline. While genetic experiments have established that the DNA damage response (DDR) pathway directs MSCI, due to limitations to the experimental systems available, mechanisms underlying MSCI remain largely unknown. Here we establish a system to study MSCI ex vivo, based on a short-term culture method, and demonstrate that active DDR signaling is required both to initiate and maintain MSCI via a dynamic and reversible process. DDR-directed MSCI follows two layers of modifications: active DDR-dependent reversible processes and irreversible histone post-translational modifications. Further, the DDR initiates MSCI independent of the downstream repressive histone mark H3K9 trimethylation (H3K9me3), thereby demonstrating that active DDR signaling is the primary mechanism of silencing in MSCI. By unveiling the dynamic nature of MSCI, and its governance by active DDR signals, our study highlights the sex chromosomes as an active signaling hub in meiosis.
2022-10-05 | GSE211519 | GEO
Project description:Meiotic synapsis and recombination ensure correct homologous segregation and genetic diversity. Asynapsed homologues are transcriptionally inactivated by meiotic silencing, which serves a surveillance function and in males drives meiotic sex chromosome inactivation. Silencing depends on the DNA damage response (DDR) network, but how DDR proteins engage repressive chromatin marks is unknown. We identify the histone H3-lysine-9 methyltransferase SETDB1 as the bridge linking the DDR to silencing in male mice. At the onset of silencing, X-chromosome H3K9 trimethylation (H3K9me3) enrichment is downstream of DDR factors. Without Setdb1, the X chromosome accrues DDR proteins but not H3K9me3. Consequently, sex chromosome remodelling and silencing fails, causing germ cell apoptosis. Our data implicate TRIM28 in linking the DDR to SETDB1, and uncover additional factors with putative meiotic XY-silencing functions. Furthermore, we show that SETDB1 imposes timely expression of meiotic and post-meiotic genes. Setdb1 thus unites the DDR network, asynapsis and meiotic chromosome silencing.
2018-11-01 | GSE107671 | GEO
Project description:Setdb1 is essential for meiotic sex chromosome inactivation in mice
| PRJNA420999 | ENA
Project description:FuHsi Maintains Nucleolar Structure and Initiates Nucleolar Biogenesis.
| PRJNA1068033 | ENA
Project description:The switch from mitosis to meiosis is a major transition that takes place during germ cell development. The precise sequence and the different gene expression programs activated during this process are only partly known. Here, we applied single-cell mRNA sequencing to interrogate the transcriptional changes that occur during the early steps of male germ cell differentiation. We isolated single cells from testes using a Dazl-GFP reporter mouse, which allowed us to focus on germ cells undergoing the mitotic to meiotic transition. We identified 4 distinct meiotic stages with unique transcriptome profiles and reconstructed the timeline of the meiotic entry in silico, from spermatogonia up to the pachytene stage, identifying transcriptional changes with an unprecedented resolution. This allowed us to characterize 3 major transitions in the meiotic prophase 1 of the male germline: meiotic entry, the meiotic sex chromosome inactivation (MSCI), and concomitant pachytene transcriptional activation. Meiotic entry is initiated following the downregulation of a tightly connected set of pluripotency factors and accompanied by a global transcriptional silencing. In contrast, during subsequent sex chromosome inactivation at the zygotene stage, gene silencing proceeds in a defined order, related to gene function.
2021-05-22 | GSE114788 | GEO
Project description:During spermatogenesis, germ cells that fail to synapse their chromosomes or fail to undergo meiotic sex chromosome inactivation (MSCI) are eliminated via apoptosis during mid-pachytene. Previous work showed that Y-linked genes Zfy1 and Zfy2 act as “executioners” for this checkpoint, and that wrongful expression of either gene during pachytene triggers germ cell death. Here, we show that in mice, Zfy genes are also necessary for efficient MSCI and the sex chromosomes are not correctly silenced in Zfy-deficient spermatocytes. In addition to this microarray data set, qPCR and RNA FISH data were used to confirm that MSCI is leaky in males lacking Zfy genes. The array data demonstrates that transgenic restoration of Zfy2 corrects the MSCI leakage phenotype. The associated RNA FISH data demonstrates that Zfy1 and Zfy2 are both able to correct the leakage phenotype.
2016-10-05 | GSE87598 | GEO
Project description:LKB1 inactivation initiates a chromatin remodeling cascade to drive metastatic progression
| PRJNA704434 | ENA
Project description:Combinatorial tumor suppressor inactivation efficiently initiates lung adenocarcinoma with therapeutic vulnerabilities
| PRJNA729736 | ENA
Project description:Meiotic sex chromosome inactivation (MSCI) is an essential event in meiotic progression in mammalian spermatogenesis. We found that La Ribonucleoprotein 7 (LARP7) is involved in MSCI. LARP7 plays a role in fetal germ cells to promote their proliferation, but is once abolished in postnatal gonocytes and re-expresses in spermatocytes at the onset of meiosis. In spermatocytes, LARP7 localizes to the XY body, a compartmentalized chromatin domain on sex chromosomes. This study aimed to elucidate a possible function of LARP7 in the XY body by using germline-specific Larp7-deficient mice.
2024-10-01 | GSE261526 | GEO
Project description:In mammalian male gametogenesis the sex chromosomes are distinctive in both gene activity and epigenetic strategy. At first meiotic prophase the heteromorphic X and Y chromosomes are placed in a separate chromatin domain called the XY body. In this process, X,Y chromatin becomes highly phosphorylated at S139 of H2AX leading to the repression of gonosomal genes, a process known as meiotic sex chromosome inactivation (MSCI), which has been studied best in mice. Post-meiotically this repression is largely maintained. Disturbance of MSCI in mice leads to harmful X,Y gene expression, eventuating in spermatocyte death and sperm heterogeneity. Sperm heterogeneity is a characteristic of the human male. For this reason we were interested in the efficiency of MSCI in human primary spermatocytes. We investigated MSCI in pachytene spermatocytes of seven probands: four infertile men and three fertile controls, using direct and indirect in situ methods. A considerable degree of variation in the degree of MSCI was detected, both between and within probands. Moreover, in post-meiotic stages this variation was observed as well, indicating survival of spermatocytes with incompletely inactivated sex chromosomes. Furthermore, we investigated the presence of H3K9me3 posttranslational modifications on the X and Y chromatin. Contrary to constitutive centromeric heterochromatin, this heterochromatin marker did not specifically accumulate on the XY body, with the exception of the heterochromatic part of the Y chromosome. This may reflect the lower degree of MSCI in man compared to mouse. These results point at relaxation of MSCI, which can be explained by genetic changes in sex chromosome composition during evolution and candidates as a mechanism behind human sperm heterogeneity.
| S-EPMC3280304 | biostudies-literature