Decoding dynamic epigenetic landscapes in human oocytes using single-cell multi-omics sequencing
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ABSTRACT:
PROVIDER: PRJNA647391 | ENA |
REPOSITORIES: ENA
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Project description:Developing female human germ cells undergo genome-wide epigenetic reprogramming, but de novo DNA methylation dynamics and their interplay with chromatin states and transcriptional activation in developing oocytes is poorly understood. Here, we developed a single-cell multi-omics sequencing method, scChaRM-seq, that enables simultaneous profiling of the DNA methylome, transcriptome, and chromatin accessibility in single human oocytes and ovarian somatic cells. We observed a global increase in DNA methylation during human oocyte growth that correlates with chromatin accessibility, whereas increases of DNA methylation at specific features were associated with active transcription. Integrated analyses of multi-omics data from humans and mice revealed species-specific gene expression, and promoter accessi- bility contributes to gene body methylation programs. Alu elements retained low DNA methylation levels and high accessibility in early growing oocytes and were located near developmental genes in humans and mice. Together, these findings show how scChaRM-seq can provide insight into DNA methylation pattern estab- lishment.
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Project description:Human spermatogenesis is a well-ordered dynamic process, which ensures the long-term production of functional spermatozoa; however, the roles of DNA methylation and chromatin accessibility in this process remain largely unknown. Here, by simultaneously investigating the chromatin accessibility, DNA methylome and transcriptome landscapes of human spermatogenesis using the modified single-cell chromatin overall omic-scale landscape sequencing approach (Modified scCOOL-seq), we revealed that the transcriptional changes throughout human spermatogenesis were correlated with the dynamic alternations of chromatin accessibility; particularly, several potential transcription factors and a set of regulatory elements involved in such process were identified. Remarkably, a round of DNA demethylation was uncovered upon meiosis initiation in human spermatogenesis, which was associated with male meiotic recombination and conserved between human and mouse. And aberrant DNA hypermethylation at recombination hotspots could be detected in leptotene spermatocytes of certain nonobstructive azoospermia patients. Functionally, the intervention of DNA demethylation affected male meiotic recombination. Collectively, this study provides multi-omics landscapes of human spermatogenesis at single-cell resolution, and offers insights into the association between DNA demethylation and male meiotic recombination.
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Project description:Human spermatogenesis is a well-ordered dynamic process, which ensures the long-term production of functional spermatozoa; however, the roles of DNA methylation and chromatin accessibility in this process remain largely unknown. Here, by simultaneously investigating the chromatin accessibility, DNA methylome and transcriptome landscapes of human spermatogenesis using the modified single-cell chromatin overall omic-scale landscape sequencing approach (Modified scCOOL-seq), we revealed that the transcriptional changes throughout human spermatogenesis were correlated with the dynamic alternations of chromatin accessibility; particularly, several potential transcription factors and a set of regulatory elements involved in such process were identified. Remarkably, a round of DNA demethylation was uncovered upon meiosis initiation in human spermatogenesis, which was associated with male meiotic recombination and conserved between human and mouse. And aberrant DNA hypermethylation at recombination hotspots could be detected in leptotene spermatocytes of certain nonobstructive azoospermia patients. Functionally, the intervention of DNA demethylation affected male meiotic recombination. Collectively, this study provides multi-omics landscapes of human spermatogenesis at single-cell resolution, and offers insights into the association between DNA demethylation and male meiotic recombination.
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Project description:The molecular mechanisms controlling the transition from meiotic arrest (germinal vesicle stage) to meiotic resumption (germinal vesicle breakdown stage) in mammalian oocytes have not been fully elucidated. Single-cell omics technology provides a new opportunity to decipher the early molecular events of oocyte maturation in mammals. Here we focused on analyzing oocytes that are collected from antral follicles of porcine puberty ovary. We used single-cell M&T-seq technology to analyze the nuclear DNA methylome and cytoplasmic transcriptome in parallel for 62 oocytes. We developed a package of pipelines for single-cell methylomics analysis, namely methyConcerto, to specifically and comprehensively characterize the methylation state and allele-specific methylation events for a single cell. We also performed 10X Genomics single-cell transcriptomic analyses to explore the bi-directional cell-cell communications within antral follicles. We characterized the gene expression and DNA methylation programs of individual oocytes in porcine antral follicle, thereby enabled defining two distinct types of oocytes, one of which is significantly more poised for maturation. Significantly differentially expressed or allele-specifically methylated genes were enriched in “RNA metabolism”, “oocyte meiosis” important signaling pathways, e.g., HIF-1/Ras/mTOR/Phospholipase D/ErbB signaling pathways etc. These results are in concert with the cellular communication results. We further confirmed Insulin Receptor Substrate-1 (IRS-1) in insulin signaling pathway is a key regulator of germinal vesicle stage oocyte maturation by in vitro maturation experiments. Our study provides new insights into the regulatory mechanisms between meiotic arrest and meiotic resumption in mammalian oocytes. We also provide a new analytical package for future single-cell methylomics study.
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Project description:The molecular mechanisms controlling the transition from meiotic arrest (germinal vesicle stage) to meiotic resumption (germinal vesicle breakdown stage) in mammalian oocytes have not been fully elucidated. Single-cell omics technology provides a new opportunity to decipher the early molecular events of oocyte maturation in mammals. Here we focused on analyzing oocytes that are collected from antral follicles of porcine puberty ovary. We used single-cell M&T-seq technology to analyze the nuclear DNA methylome and cytoplasmic transcriptome in parallel for 62 oocytes. We developed a package of pipelines for single-cell methylomics analysis, namely methyConcerto, to specifically and comprehensively characterize the methylation state and allele-specific methylation events for a single cell. We also performed 10X Genomics single-cell transcriptomic analyses to explore the bi-directional cell-cell communications within antral follicles. We characterized the gene expression and DNA methylation programs of individual oocytes in porcine antral follicle, thereby enabled defining two distinct types of oocytes, one of which is significantly more poised for maturation. Significantly differentially expressed or allele-specifically methylated genes were enriched in “RNA metabolism”, “oocyte meiosis” important signaling pathways, e.g., HIF-1/Ras/mTOR/Phospholipase D/ErbB signaling pathways etc. These results are in concert with the cellular communication results. We further confirmed Insulin Receptor Substrate-1 (IRS-1) in insulin signaling pathway is a key regulator of germinal vesicle stage oocyte maturation by in vitro maturation experiments. Our study provides new insights into the regulatory mechanisms between meiotic arrest and meiotic resumption in mammalian oocytes. We also provide a new analytical package for future single-cell methylomics study.
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Project description:Human spermatogenesis is a well-ordered dynamic process, which ensures the long-term production of functional spermatozoa; however, the roles of DNA methylation and chromatin accessibility in this process remain largely unknown. Here, by simultaneously investigating the chromatin accessibility, DNA methylome and transcriptome landscapes of human spermatogenesis using the modified single-cell chromatin overall omic-scale landscape sequencing approach (Modified scCOOL-seq), we revealed that the transcriptional changes throughout human spermatogenesis were correlated with the dynamic alternations of chromatin accessibility; particularly, several potential transcription factors and a set of regulatory elements involved in such process were identified. Remarkably, a round of DNA demethylation was uncovered upon meiosis initiation in human spermatogenesis, which was associated with male meiotic recombination and conserved between human and mouse. And aberrant DNA hypermethylation at recombination hotspots could be detected in leptotene spermatocytes of certain nonobstructive azoospermia patients. Functionally, the intervention of DNA demethylation affected male meiotic recombination. Collectively, this study provides multi-omics landscapes of human spermatogenesis at single-cell resolution, and offers insights into the association between DNA demethylation and male meiotic recombination.
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Project description:The human spinal cord contains diverse cell types, governed by a series of spatiotemporal events for tissue assembly and functions. However, the regulation of cell fate specification in the human developing spinal cord remains largely unknown. By performing single-cell and spatial multi-omics methods, we integrated the datasets and created a comprehensive human developmental atlas of the first trimester spinal cord. Unexpectedly, we discovered unique events in human spinal cord development, including early loss of active neural stem cells, simultaneous occurrence of neurogenesis and gliogenesis, and distinct spatiotemporal genetic regulations of fate choices. We also identified distinct regulations of cancer stem cells in ependymomas from our atlas. Thus, we demonstrate spatiotemporal genetic regulation of human spinal cord development and its potential to understand novel disease mechanisms.
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