UHRF1 interacts with snRNAs and regulates alternative splicing in mouse spermatogonial stem cells

Zhou, Shumin; Dong, Juan; Xiong, Mengneng; Gan, Shiming; Wen, Yujiao; Zhang, Jin; Wang, Xiaoli; Yuan, Shuiqiao; Gui, Yaoting

doi:10.1016/j.stemcr.2022.06.010

Cited by 10 publications

(11 citation statements)

References 52 publications

(61 reference statements)

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“…In recent years, it has been reported that many spermatogonia-related gene deletions have disrupted SSC self-renewal and differentiation in patient and mouse models (La and Hobbs, 2019a; Tan and Wilkinson, 2020; Wang et al, 2021). SCOS was observed in Ddx5 , Tial1 / Tiar , Uhrf1 , Pramef12 , Dot1l , and Rad51 deletion mouse models (Beck et al ., 1998; Legrand et al ., 2019; Lin et al, 2022; Qin et al, 2022; Wang et al, 2019; Zhou et al ., 2022). Mouse models are still of great significance and reference for human SCOS studies, and they will provide a better understanding of how SCOS occurs and develops over time.…”

Section: Discussionmentioning

confidence: 99%

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Splicing factor SRSF1 is essential for homing of precursor spermatogonial stem cells in mice

Sun

Zheng

Chen

et al. 2023

Preprint

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Spermatogonial stem cells (SSCs) are essential for continuous spermatogenesis and male fertility. The underlying mechanisms of alternative splicing (AS) in mouse SSCs are still largely unclear. We demonstrated that SRSF1 is essential for gene expression and splicing in mouse SSCs. Crosslinking immunoprecipitation and sequencing (CLIP-seq) data revealed that spermatogonia-related genes (e.g.,Plzf,Id4,Setdb1,Stra8,Tial1/Tiar,Bcas2,Ddx5,Srsf10,Uhrf1, andBud31) were bound by SRSF1 in the mouse testes. Specific deletion ofSrsf1in mouse germ cells impairs homing and self-renewal of SSCs leading to male infertility. Whole-mount staining data showed the absence of germ cells in the testes of adult cKO mice, which indicates Sertoli cell-only syndrome (SCOS) in cKO mice. The expression of spermatogonia-related genes (Gfra1,Pou5f1,Plzf,Dnd1,Stra8, andTaf4b) was significantly reduced in the testes of conditional knockout (cKO) mice. Moreover, multiomics analysis suggests that SRSF1 directly binds and regulates the expression ofTial1/Tiarvia AS to implement SSC homing and self-renewal. In addition, immunoprecipitation mass spectrometry (IP-MS) data showed that SRSF1 interacts with RNA splicing-related proteins (e.g., SRSF10, SART1, RBM15, SRRM2, SF3B6, and SF3A2). Collectively, our data reveal the critical role of SRSF1-mediated AS in SSC homing and self-renewal, which may provide a framework to elucidate the molecular mechanisms of the posttranscriptional network underlying the formation of SSC pools and the establishment of niches.

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Section: Discussionmentioning

confidence: 99%

“…Surprisingly, recent studies have found that the RNA-binding proteins SRSF10, UHRF1, BUD31, and BCAS2 regulate alternative splicing (AS) in mouse spermatogonia (Liu et al, 2022;Liu et al, 2017;Qin et al, 2023;Zhou et al, 2022). It is well known that testes are rich in AS events (Mazin et al, 2021;Venables, 2002).…”

Section: Introductionmentioning

confidence: 99%

Splicing factor SRSF1 is essential for homing of precursor spermatogonial stem cells in mice

Sun

Zheng

Chen

et al. 2023

Preprint

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“…In particular, although many studies have described the molecular mechanism of the self-renewal and differentiation of SSCs (Makela and Hobbs, 2019;Zhou et al, 2022;Zhou et al, 2021), the study that focuses on SSC pool establishment is limited and the molecular mechanism under ProSG to SSC transition is largely unknown. In the current study, we conditionally knocked out hnRNPU in ProSG to study the progression of ProSG to SSCs transition.…”

Section: Discussionmentioning

confidence: 99%

Sertoli cell-only phenotype and scRNA-seq reveal hnRNPU as a regulator required for spermatogonial stem cell pool establishment in mice

Yuan

Wen

Zhou

et al. 2022

Preprint

Self Cite

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The continuous regeneration of spermatogonial stem cells (SSCs) underpins spermatogenesis and lifelong male fertility; however, little is known about the developmental origins of the SSC pool. Here, we document that heterogeneous nuclear ribonucleoprotein U (hnRNPU) is essential for establishing the SSC pool. In male mice, conditional loss of hnRNPU in prospermatogonia (ProSG) arrests spermatogenesis and results in sterility, characterized by complete loss of germ cells around postnatal day 10, which resembles the Sertoli cell-only phenotype in humans. hnRNPU-deficient ProSG fails to differentiate and migrate to the basement membrane to establish SSC pool in infancy. Moreover, we find that the deletion of hnRNPU leads to the accumulation of ProSG and the reduction of undifferentiated spermatogonia and further disrupts the process of T1-ProSG to T2-ProSG transition. hnRNPU-deficiency in ProSG deregulates the expression of spermatogenic-related genes and destroys the alternative splicing of genes related to cell cycles, and single-cell transcriptional analyses reveal germ cells are in a mitotically quiescent state and lost their unique identity upon hnRNPU deletion. We further show that hnRNPU could interact with DDX5, SRSF3, and TRIM28 proteins and bind to Vrk1, Slx4, and Dazl transcripts with identified to be suffered aberrant alternative splicing in hnRNPU-deficient testes. These observations give important insights into SSC pool establishment and may have translational implications for male fertility.

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“…Previous studies have identified the key RNA-binding proteins DND1 and DDX5 in SSCs with a unique and dominant role in posttranscriptional regulation ( Legrand et al, 2019 ; Yamaji et al, 2017 ). Surprisingly, recent studies have found that the RNA-binding proteins SRSF10, UHRF1, BUD31, and BCAS2 regulate alternative splicing (AS) in mouse spermatogonia ( Liu et al, 2022 ; Liu et al, 2017 ; Qin et al, 2023 ; Zhou et al, 2022 ). It is well known that testes are rich in AS events ( Mazin et al, 2021 ; Venables, 2002 ).…”

Section: Introductionmentioning

confidence: 99%

Splicing factor SRSF1 is essential for homing of precursor spermatogonial stem cells in mice

Sun,

Lv,

Chen

et al. 2024

eLife

View full text Add to dashboard Cite

Spermatogonial stem cells (SSCs) are essential for continuous spermatogenesis and male fertility. The underlying mechanisms of alternative splicing (AS) in mouse SSCs are still largely unclear. We demonstrated that SRSF1 is essential for gene expression and splicing in mouse SSCs. Crosslinking immunoprecipitation and sequencing (CLIP-seq) data revealed that spermatogonia-related genes (e.g., Plzf, Id4, Setdb1, Stra8, Tial1/Tiar, Bcas2, Ddx5, Srsf10, Uhrf1, and Bud31) were bound by SRSF1 in the mouse testes. Specific deletion of Srsf1 in mouse germ cells impairs homing and self-renewal of SSCs leading to male infertility. Whole-mount staining data showed the absence of germ cells in the testes of adult cKO mice, which indicates Sertoli cell-only syndrome (SCOS) in cKO mice. The expression of spermatogonia-related genes (Gfra1, Pou5f1, Plzf, Dnd1, Stra8, and Taf4b) was significantly reduced in the testes of conditional knockout (cKO) mice. Moreover, multiomics analysis suggests that SRSF1 directly binds and regulates the expression of Tial1/Tiar via AS to implement SSC homing and self-renewal. In addition, immunoprecipitation mass spectrometry (IP-MS) data showed that SRSF1 interacts with RNA splicing-related proteins (e.g., SRSF10, SART1, RBM15, SRRM2, SF3B6, and SF3A2). Collectively, our data reveal the critical role of SRSF1-mediated AS in SSC homing and self-renewal, which may provide a framework to elucidate the molecular mechanisms of the posttranscriptional network underlying the formation of SSC pools and the establishment of niches.

show abstract

UHRF1 interacts with snRNAs and regulates alternative splicing in mouse spermatogonial stem cells

Cited by 10 publications

References 52 publications

Splicing factor SRSF1 is essential for homing of precursor spermatogonial stem cells in mice

Splicing factor SRSF1 is essential for homing of precursor spermatogonial stem cells in mice

Sertoli cell-only phenotype and scRNA-seq reveal hnRNPU as a regulator required for spermatogonial stem cell pool establishment in mice

Splicing factor SRSF1 is essential for homing of precursor spermatogonial stem cells in mice

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