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Single-Cell RNA Sequencing Analysis Reveals Sequential Cell Fate Transition during Human Spermatogenesis

ABSTRACT: Single-Cell RNA Sequencing Analysis Reveals Sequential Cell Fate Transition during Human Spermatogenesis

PROVIDER: PRJNA417066 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6253470_1.fastq.gz	Fastqsanger.gz
	SRR6253470_2.fastq.gz	Fastqsanger.gz
	SRR6253480_1.fastq.gz	Fastqsanger.gz
	SRR6253480_2.fastq.gz	Fastqsanger.gz
	SRR6253490_1.fastq.gz	Fastqsanger.gz

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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.

Project description:Kollarovic2016 - Cell fate decision at G1-S transition This model is described in the article: To senesce or not to senesce: how primary human fibroblasts decide their cell fate after DNA damage. Kollarovic G, Studencka M, Ivanova L, Lauenstein C, Heinze K, Lapytsko A, Talemi SR, Figueiredo AS, Schaber J. Aging (Albany NY) 2016 Jan; Abstract: Excessive DNA damage can induce an irreversible cell cycle arrest, called senescence, which is generally perceived as an important tumour-suppressor mechanism. However, it is unclear how cells decide whether to senesce or not after DNA damage. By combining experimental data with a parameterized mathematical model we elucidate this cell fate decision at the G1-S transition. Our model provides a quantitative and conceptually new understanding of how human fibroblasts decide whether DNA damage is beyond repair and senesce. Model and data imply that the G1-S transition is regulated by a bistable hysteresis switch with respect to Cdk2 activity, which in turn is controlled by the Cdk2/p21 ratio rather than cyclin abundance. We experimentally confirm the resulting predictions that to induce senescence i) in healthy cells both high initial and elevated background DNA damage are necessary and sufficient, and ii) in already damaged cells much lower additional DNA damage is sufficient. Our study provides a mechanistic explanation of a) how noise in protein abundances allows cells to overcome the G1-S arrest even with substantial DNA damage, potentially leading to neoplasia, and b) how accumulating DNA damage with age increasingly sensitizes cells for senescence. This model is hosted on BioModels Database and identified by: BIOMD0000000632. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Single-Cell RNA Sequencing Analysis Reveals Sequential Cell Fate Transition during Human Spermatogenesis

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