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Single-cell multi-omics sequencing reveals the epigenomic landscapes in human spermatogenesis [STRT-seq; scCOOL-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235321 | GEO | 2023/07/09

REPOSITORIES: GEO

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Project description:Spermatogenesis generates mature male gametes and is critical for the proper transmission of genetic information between generations. However, the developmental landscape and underlying molecular signals during human spermatogenesis remain unknown. Here, we examined human spermatogenesis using transcriptome-wide single-cell RNA sequencing of 2,854 individual testicular cells from donors with normal spermatogenesis (donors with normal fertility or OA) and 174 testicular cells from one donor diagnosed as having nonobstructive azoospermia (NOA). Systematic bioinformatics analyses enabled us to delineate the full developmental trajectories of human spermatogenesis. A hierarchical model was established, which was characterized by the sequential and step-wise development of three spermatogonia subtypes, seven spermatocyte subtypes, and four spermatid subtypes. Furthermore, we recapitulated key hallmarks of human spermatogenesis at the single-cell level, including spermatogonial development, mitosis-to-meiosis transition, meiotic recombination, meiotic sex chromosome inactivation, and histone-to-protamine exchange. Remarkably, BMPR1B and FGFR3 were identified as novel markers of human spermatogonial stem cells, indicating the potentially critical role of BMP and FGF signaling pathways for SSC maintenance. Further analysis identified several novel marker genes of specific cell type such as HMGA1, PIWIL4, TEX29, SCML1, and CCDC112, the expression patterns of which were confirmed via RNA FISH or immunostaining. We also demonstrated that scRNA-seq provided a platform to find differentially expressed genes correlated with one type of nonobstructive azoospermia (NOA) at the genome-wide transcriptional profiling level, which might pave way for further diagnosis and dissecting the underlying mechanisms of male infertility. Our work allows for the reconstruction of transcriptional programs inherent to sequential cell fate transition during human spermatogenesis and has implications for deciphering male-related reproductive disorders.

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Single-cell multi-omics sequencing reveals the epigenomic landscapes in human spermatogenesis [STRT-seq; scCOOL-seq]

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