A regulatory role for CHD4 in maintenance of the spermatogonial stem cell pool
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA684464 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13241710.fastq.gz | Fastqsanger.gz | |||
| SRR13241711.fastq.gz | Fastqsanger.gz |
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Project description:Maintenance and self-renewal of the spermatogonial stem cell (SSC) population is the cornerstone of male fertility. In this manuscript we have identified a key role for the nucleosome remodelling protein Chromodomain Helicase DNA binding protein 4 (CHD4) in regulating SSC function. Gene expression analyses revealed that CHD4 expression is largely restricted to spermatogonia in the mouse testis, and is particularly enriched in SSCs. Using spermatogonial transplantation techniques and RNAi mediated knockdown it was established that loss of Chd4 expression significantly impairs SSC regenerative capacity, resulting in a ~50% reduction in colonisation of recipient testes. A single cell RNA-seq comparison depicted reduced expression of ‘self-renewal’ genes such as Gfra1 and Pten following Chd4 knockdown, along with increased expression of signature progenitor genes, Neurog3 and Dazl. Co-immunoprecipitation analyses demonstrated that CHD4 regulates gene expression in spermatogonia not only though its traditional association with the remodelling complex NuRD, but also via interaction with the GDNF-responsive transcription factor SALL4. Cumulatively, the results of this study depict a previously unappreciated fundamental role for CHD4 in controlling fate decisions in the spermatogonial pool.
2021-06-17 | PXD022066 | Pride
Project description:To understand the role of the nucleosome remodelling protein CHD4 in regulating spermatogonial stem cell function, we performed single cell RNA-sequencing on undifferentiated spermatogonia from primary culture that had been transfected with either control (non-targeting) siRNA or Chd4 siRNA. Transcriptome profiling revealed reduced expression of ‘self-renewal’ genes following Chd4 knockdown, along with increased expression of signature progenitor genes. Overall, CHD4 was demonstrated to primarily act as an activator of gene expression in SSCs. In pairing these data with additional analyses, including use of an Id4-eGfp transgenic mouse line, spermatogonial transplantation, and co-immunoprecipitation experiments: the findings of our study demonstrated a previously unappreciated and fundamental role for CHD4 in controlling fate decisions in the spermatogonial pool.
2021-05-06 | GSE163027 | GEO
Project description:Maintenance and self-renewal of the spermatogonial stem cell (SSC) population is the cornerstone of male fertility. Here, we have identified a key role for the nucleosome remodeling protein CHD4 in regulating SSC function. Gene expression analyses revealed that CHD4 expression is highly enriched in the SSC population in the mouse testis. Using spermatogonial transplantation techniques it was established that loss of Chd4 expression significantly impairs SSC regenerative capacity, causing a ∼50% reduction in colonization of recipient testes. An scRNA-seq comparison revealed reduced expression of "self-renewal" genes following Chd4 knockdown, along with increased expression of signature progenitor genes. Co-immunoprecipitation analyses demonstrated that CHD4 regulates gene expression in spermatogonia not only through its traditional association with the remodeling complex NuRD, but also via interaction with the GDNF-responsive transcription factor SALL4. Cumulatively, the results of this study depict a previously unappreciated role for CHD4 in controlling fate decisions in the spermatogonial pool.
| S-EPMC8190575 | biostudies-literature
Project description:Male spermatogenesis is sustained by homeostatic balance between the self-renewal and differentiation of spermatogonial stem cells (SSCs), which is dependent on the strict regulation of transcriptional factor and chromatin modulator gene expression. Chromodomain helicase DNA-binding protein 4 (CHD4) is highly expressed in SSCs but roles in mouse spermatogenesis are unexplored. Here, we report that the germ-cell-specific deletion of Chd4 resulted in complete infertility in male mice, with rapid loss of SSCs and excessive germ cell apoptosis. Chd4-knockdown in cultured SSCs also promoted the expression of apoptosis-related genes and thereby activated the tumor necrosis factor signaling pathway. Mechanistically, CHD4 occupies the genomic regulatory region of key apoptosis-related genes including Jun and Nfkb1. Together, our findings reveal the determinant role of CHD4 in SSCs survival in vivo, which will offer insight into the pathogenesis of male sterility and potential novel therapeutic targets.
2022-01-08 | GSE193070 | GEO
Project description:Male spermatogenesis is sustained by homeostatic balance between the self-renewal and differentiation of spermatogonial stem cells (SSCs), which is dependent on the strict regulation of transcriptional factor and chromatin modulator gene expression. Chromodomain helicase DNA-binding protein 4 (CHD4) is highly expressed in SSCs but roles in mouse spermatogenesis are unexplored. Here, we report that the germ-cell-specific deletion of Chd4 resulted in complete infertility in male mice, with rapid loss of SSCs and excessive germ cell apoptosis. Chd4-knockdown in cultured SSCs also promoted the expression of apoptosis-related genes and thereby activated the tumor necrosis factor signaling pathway. Mechanistically, CHD4 occupies the genomic regulatory region of key apoptosis-related genes including Jun and Nfkb1. Together, our findings reveal the determinant role of CHD4 in SSCs survival in vivo, which will offer insight into the pathogenesis of male sterility and potential novel therapeutic targets.
2022-01-08 | GSE193069 | GEO
Project description:To understand the functional role of CHD4, a member of the Nucleosome Remodeling and Deacetylase (NuRD) complex, in establishing chromatin states in the formation and maintenance of ovarian reserve and the maintenance of female and male germ cells, we eliminated CHD4 function in germ cells using Ddx4-Cre and Gdf9-iCre to generate CHD4 conditional knockout (Chd4 DcKO and GcKO) mice. We discover that CHD4 defines the chromatin state that ensures germ cell survival, thereby enabling the long-term maintenance of female and male germ cells. We then performed ATAC-seq in Chd4 Dctrl and Chd4 DcKO non-growing oocytes and undifferentiated spermatogonia.
2024-09-27 | GSE273308 | GEO
Project description:To understand the functional role of CHD4, a member of the Nucleosome Remodeling and Deacetylase (NuRD) complex, in establishing chromatin states in the formation and maintenance of ovarian reserve and the maintenance of female and male germ cells, we eliminated CHD4 function in germ cells using Ddx4-Cre and Gdf9-iCre to generate CHD4 conditional knockout (Chd4 DcKO and GcKO) mice. We discover that CHD4 defines the chromatin state that ensures germ cell survival, thereby enabling the long-term maintenance of female and male germ cells. We then performed CUT&Tag for CHD4 in Chd4 f/f P1 oocytes.
2024-09-27 | GSE273307 | GEO
Project description:To understand the functional role of CHD4, a member of the Nucleosome Remodeling and Deacetylase (NuRD) complex, in establishing chromatin states in the formation and maintenance of ovarian reserve and the maintenance of female and male germ cells, we eliminated CHD4 function in germ cells using Ddx4-Cre and Gdf9-iCre to generate CHD4 conditional knockout (Chd4 DcKO and GcKO) mice. We discover that CHD4 defines the chromatin state that ensures germ cell survival, thereby enabling the long-term maintenance of female and male germ cells. We then performed gene expression profiling analysis using data obtained from RNA-seq of Chd4 Dctrl and Chd4 DcKO non-growing oocytes and undifferentiated spermatogonia, and Chd4 Gctrl and Chd4 GcKO non-growing and growing oocytes.
2024-09-27 | GSE273306 | GEO
Project description:DDX20 is required to promote spermatogonial stem cell pool formation by regulating mRNA translation during postnatal prospermatogonia differentiation in mice.
2024-02-01 | GSE244755 | GEO
Project description:Glioblastomas (GBM) harbor subpopulations of therapy-resistant tumor initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397-kDa transcription factor. ZFHX4 is required to maintain TIC-associated phenotypes in vitro, suggesting that ZFHX4 regulates TIC differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the NuRD (nucleosome remodeling and deacetylase) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we demonstrate ZFHX4 is a master regulator of CHD4-mediated gene expression. These observations define ZFHX4 as a regulatory factor that links the chromatin remodeling NuRD complex and the GBM TIC state. Examination of binding of ZFHX4 and CHD4 across the human genome, using the 0308 tumor initiating cell line. Two replicates for each protein, compared to whole cell extract inputs.
2014-01-16 | E-GEOD-52419 | biostudies-arrayexpress