Genome-wide transcriptional silencing and mRNA stabilization allow the coordinated expression of the meiotic program in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE261062 | GEO | 2025/03/26
REPOSITORIES: GEO
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Project description:The DSB-machinery, which induces the programmed DNA double-strand breaks (DSBs) in leptotene and zygotene stages during meiosis, needs to be kept in silence after the initiation of pachytene stage to prevent the activation of DSB checkpoint that may lead to meiotic arrest or apoptosis of germ cells. However, the mechanisms underlying this repression remain largely unknown. Here, we report that ZFP541, a germ cell-specific zinc finger protein, is responsible for the suppression of DSBs formation at late pachytene. Lack of Zfp541 in mice leads to generation of DSBs in late pachytene spermatocytes by DSB formation related-proteins and causes male infertility due to meiotic failure. Plated-based scRNA-seq of Zfp541-/- spermatocytes revealed that ZFP541 negatively regulates many meiotic prophase genes, including genes for DSB formation and their upstream transcriptional regulators, in late pachytene spermatocytes. These results were confirmed by 10x single-cell RNA-seq data on spermatogenesis of Zfp541-/- testes, which suggested that Zfp541 is required for repressing the activation of pre-pachytene gene expression programs from early to late pachytene. ZFP541 ChIP-seq on pachytene and diplotene spermatocytes demonstrated that ZFP541 occupies the promoters of meiosis initiators (e.g., Meiosin and Rxra) and a subset of their downstream genes to repress their transcription, and thus prevent the reactivation of pre-pachytene gene expression programs in pachytene spermatocytes. Thus, our results not only revealed the role of ZFP541 in maintaining the repression of pre-pachytene transcriptional programs in pachytene spermatocytes but also provide new insight into the regulation of meiotic progression by timely turning off pre-pachytene genes.
2021-04-16 | GSE172171 | GEO
Project description:The DSB-machinery, which induces the programmed DNA double-strand breaks (DSBs) in leptotene and zygotene stages during meiosis, needs to be kept in silence after the initiation of pachytene stage to prevent the activation of DSB checkpoint that may lead to meiotic arrest or apoptosis of germ cells. However, the mechanisms underlying this repression remain largely unknown. Here, we report that ZFP541, a germ cell-specific zinc finger protein, is responsible for the suppression of DSBs formation at late pachytene. Lack of Zfp541 in mice leads to generation of DSBs in late pachytene spermatocytes by DSB formation related-proteins and causes male infertility due to meiotic failure. Plated-based scRNA-seq of Zfp541-/- spermatocytes revealed that ZFP541 negatively regulates many meiotic prophase genes, including genes for DSB formation and their upstream transcriptional regulators, in late pachytene spermatocytes. These results were confirmed by 10x single-cell RNA-seq data on spermatogenesis of Zfp541-/- testes, which suggested that Zfp541 is required for repressing the activation of pre-pachytene gene expression programs from early to late pachytene. ZFP541 ChIP-seq on pachytene and diplotene spermatocytes demonstrated that ZFP541 occupies the promoters of meiosis initiators (e.g., Meiosin and Rxra) and a subset of their downstream genes to repress their transcription, and thus prevent the reactivation of pre-pachytene gene expression programs in pachytene spermatocytes. Thus, our results not only revealed the role of ZFP541 in maintaining the repression of pre-pachytene transcriptional programs in pachytene spermatocytes but also provide new insight into the regulation of meiotic progression by timely turning off pre-pachytene genes.
2021-04-16 | GSE172157 | GEO
Project description:The DSB-machinery, which induces the programmed DNA double-strand breaks (DSBs) in leptotene and zygotene stages during meiosis, needs to be kept in silence after the initiation of pachytene stage to prevent the activation of DSB checkpoint that may lead to meiotic arrest or apoptosis of germ cells. However, the mechanisms underlying this repression remain largely unknown. Here, we report that ZFP541, a germ cell-specific zinc finger protein, is responsible for the suppression of DSBs formation at late pachytene. Lack of Zfp541 in mice leads to generation of DSBs in late pachytene spermatocytes by DSB formation related-proteins and causes male infertility due to meiotic failure. Plated-based scRNA-seq of Zfp541-/- spermatocytes revealed that ZFP541 negatively regulates many meiotic prophase genes, including genes for DSB formation and their upstream transcriptional regulators, in late pachytene spermatocytes. These results were confirmed by 10x single-cell RNA-seq data on spermatogenesis of Zfp541-/- testes, which suggested that Zfp541 is required for repressing the activation of pre-pachytene gene expression programs from early to late pachytene. ZFP541 ChIP-seq on pachytene and diplotene spermatocytes demonstrated that ZFP541 occupies the promoters of meiosis initiators (e.g., Meiosin and Rxra) and a subset of their downstream genes to repress their transcription, and thus prevent the reactivation of pre-pachytene gene expression programs in pachytene spermatocytes. Thus, our results not only revealed the role of ZFP541 in maintaining the repression of pre-pachytene transcriptional programs in pachytene spermatocytes but also provide new insight into the regulation of meiotic progression by timely turning off pre-pachytene genes.
2021-04-16 | GSE172160 | GEO
Project description:Post-transcriptional regulation of gene expression by RNA-binding proteins helps facilitate fast, clean transitions from one cell state to the next during germ cell differentiation. Previously we showed that the RNA helicase YTHDC2 is required for germ cells to properly switch from mitosis to meiosis (Bailey et al., 2017). While YTHDC2 protein is first expressed as male germ cells enter meiosis, when it is needed to shut down the mitotic program, YTHDC2 expression continues to increase and reaches its highest levels later in meiotic prophase, in pachytene spermatocytes. Here we show that YTHDC2 has an additional essential role regulating meiotic progression in late spermatocytes during mouse germ cell differentiation. Inducing conditional knockout of Ythdc2 during the first wave of spermatogenesis, after the germ cells have already initiated meiotic prophase, allowed Ythdc2-deficient germ cells to successfully reach the pachytene stage and properly express many meiotic markers. However, instead of continuing through meiotic prophase and initiating the meiotic divisions, late pachytene spermatocytes failed to transition to the diplotene stage and quickly died. Loss of function of Ythdc2 in spermatocytes resulted in changes in transcript levels for a number of genes by RNA-sequencing compared to control spermatocytes. Our findings suggest that YTHDC2 facilitates proper progression of germ cells through multiple steps of meiosis, potentially via several mechanisms of post-transcriptional RNA regulation.
2023-03-02 | GSE222283 | GEO
Project description:Mechanism for controlled assembly of transcriptional condensates by Aire [5'-ethynyl uridine RNA-seq]
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Project description:In mammals, piRNA populations are dynamic throughout male germ cell development. Embryonic piRNAs consist of both primary and secondary species and are mainly directed toward transposons. In meiotic cells, however, the piRNA population is transposon-poor and restricted to primary piRNAs derived from pachytene piRNA clusters. The mechanism controlling which piRNAs are present at each developmental stage is poorly understood. Here we show that RNF17 shapes adult meiotic piRNA content by suppressing the production of secondary piRNAs. In the absence of RNF17, ping-pong (secondary amplification) occurs inappropriately in meiotic cells – aberrantly targeting protein-coding genes and lncRNAs. Our data indicate that RNF17 comprises one component of a “refereeing” mechanism that prevents deleterious activity of the meiotic piRNA pathway by ensuring the selective loading of PIWI proteins with products of meiotic piRNA clusters. Examination of small RNA profile in heterozygous and homozygous RNF17 adult testes, pachytene or round spermatid sorted cells
2014-12-17 | E-GEOD-53917 | biostudies-arrayexpress
Project description:During embryonic germ cell development in mice, transposon-enriched, piwi-interacting RNAs (piRNAs) guide MILI and MIWI2 to direct silencing of potentially active mobile element families. In contrast, we know much less about the function of the highly abundant and extremely diverse class of piRNAs, which partner with MIWI and MILI during meiosis. Both MIWI and its catalytic activity are required for successful spermatogenesis, strongly indicating that piRNA-guided cleavage is critical for germ cell development. To gain an understanding of meiotic piRNA targets, we augmented the mouse piRNA repertoire by introducing an entire human meiotic piRNA cluster. This triggered a spermatogenesis defect, presumably by inappropriately targeting the piRNA machinery to mouse RNAs essential for germ cell development. Through an analysis of such de novo targets, we derived a signature for pachytene piRNA target recognition. This enabled identification of both transposable elements and meiotically expressed protein coding genes as targets of native piRNAs. Cleavage of genic targets begins at the pachytene stage when meiotic piRNAs first appear. As such, target mRNA levels attenuate starting from the pachytene stage and are further repressed throughout meiosis. Target mRNA-piRNA pairs also show evidence of an ongoing cleavage-dependent amplification cycle, which is not normally a strong feature of meiotic piRNAs. Our data support the idea that meiotic piRNA populations must be strongly selected to enable successful spermatogenesis, both driving the response away from essential genes and directing the pathway toward mRNA targets that are regulated by small RNAs in meiotic cells. 48 samples
2015-05-22 | E-GEOD-64138 | biostudies-arrayexpress
Project description:Pachytene piRNAs control male fertility across metazoans, yet mechanisms through which they govern meiosis I in pachytene remain unclear. We demonstrate, in C. elegans, that homolog pairing, and crossover formation are compromised in the absence of piRNA function. We identify several protein coding genes as targets of piRNAs including Polo like kinase 3 (PLK-). Pachytene piRNAs spatially restrict and exclude PLK-3 expression from meiosis I. Expansion of PLK-3 expression into the pachytene region, upon loss of piRNAs, is reflected in meiotic defects, which are partially rescued by removal of ectopic PLK-3. Pachytene piRNAs regulate PLK-3 through both translational repression and post-transcriptional degradation establishing the spatiotemporal control of gene expression. Given the conserved role of pachytene piRNAs, we propose that these mechanisms may be applicable to mammals.
2023-10-14 | GSE245020 | GEO
Project description:Pachytene piRNAs control male fertility across metazoans, yet mechanisms through which they govern meiosis I in pachytene remain unclear. We demonstrate, in C. elegans, that homolog pairing, and crossover formation are compromised in the absence of piRNA function. We identify several protein coding genes as targets of piRNAs including Polo like kinase 3 (PLK-). Pachytene piRNAs spatially restrict and exclude PLK-3 expression from meiosis I. Expansion of PLK-3 expression into the pachytene region, upon loss of piRNAs, is reflected in meiotic defects, which are partially rescued by removal of ectopic PLK-3. Pachytene piRNAs regulate PLK-3 through both translational repression and post-transcriptional degradation establishing the spatiotemporal control of gene expression. Given the conserved role of pachytene piRNAs, we propose that these mechanisms may be applicable to mammals.
2023-10-14 | GSE245023 | GEO
Project description:Pachytene piRNAs control male fertility across metazoans, yet mechanisms through which they govern meiosis I in pachytene remain unclear. We demonstrate, in C. elegans, that homolog pairing, and crossover formation are compromised in the absence of piRNA function. We identify several protein coding genes as targets of piRNAs including Polo like kinase 3 (PLK-). Pachytene piRNAs spatially restrict and exclude PLK-3 expression from meiosis I. Expansion of PLK-3 expression into the pachytene region, upon loss of piRNAs, is reflected in meiotic defects, which are partially rescued by removal of ectopic PLK-3. Pachytene piRNAs regulate PLK-3 through both translational repression and post-transcriptional degradation establishing the spatiotemporal control of gene expression. Given the conserved role of pachytene piRNAs, we propose that these mechanisms may be applicable to mammals.
2024-07-12 | GSE271910 | GEO