Transcription Factor E4F1 Dictates Spermatogonial Stem Cell Fate Decisions by Regulating Mitochondrial Functions and Cell Cycle Progression

Overview

Journal Cell Biosci

Publisher Biomed Central

Specialty Biology

Date 2023 Sep 25

PMID 37749649

Authors

Rong-Ge Yan

Zhen He

Fei-Chen Wang

Shuang Li

Qin-Bang Shang

Qi-En Yang

Affiliations

Soon will be listed here.

Abstract

Background: Spermatogonial stem cells (SSCs) provide a foundation for robust and continual spermatogenesis in mammals. SSCs self-renew to maintain a functional stem cell pool and differentiate to supply committed progenitors. Metabolism acts as a crucial determinant of stem cell fates; however, factors linking metabolic programs to SSC development and maintenance are poorly understood.

Results: We analyzed the chromatin accessibility of undifferentiated spermatogonia at the single-cell level and identified 37 positive TF regulators that may have potential roles in dictating SSC fates. The transcription factor E4F1 is expressed in spermatogonia, and its conditional deletion in mouse germ cells results in progressive loss of the entire undifferentiated spermatogonial pool. Single-cell RNA-seq analysis of control and E4f1-deficient spermatogonia revealed that E4F1 acts as a key regulator of mitochondrial function. E4F1 binds to promotors of genes that encode components of the mitochondrial respiratory chain, including Ndufs5, Cox7a2, Cox6c, and Dnajc19. Loss of E4f1 function caused abnormal mitochondrial morphology and defects in fatty acid metabolism; as a result, undifferentiated spermatogonia were gradually lost due to cell cycle arrest and elevated apoptosis. Deletion of p53 in E4f1-deficient germ cells only temporarily prevented spermatogonial loss but did not rescue the defects in SSC maintenance.

Conclusions: Emerging evidence indicates that metabolic signals dictate stem cell fate decisions. In this study, we identified a list of transcription regulators that have potential roles in the fate transitions of undifferentiated spermatogonia in mice. Functional experiments demonstrated that the E4F1-mediated transcription program is a crucial regulator of metabolism and SSC fate decisions in mammals.

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References

Varuzhanyan G, Rojansky R, Sweredoski M, Graham R, Hess S, Ladinsky M . Mitochondrial fusion is required for spermatogonial differentiation and meiosis. Elife. 2019; 8. PMC: 6805159. DOI: 10.7554/eLife.51601. View

Morimoto H, Iwata K, Ogonuki N, Inoue K, Atsuo O, Kanatsu-Shinohara M . ROS are required for mouse spermatogonial stem cell self-renewal. Cell Stem Cell. 2013; 12(6):774-86. DOI: 10.1016/j.stem.2013.04.001. View

Lord T, Nixon B . Metabolic Changes Accompanying Spermatogonial Stem Cell Differentiation. Dev Cell. 2020; 52(4):399-411. DOI: 10.1016/j.devcel.2020.01.014. View

Grote D, Moison C, Duhamel S, Chagraoui J, Girard S, Yang J . E4F1 is a master regulator of CHK1-mediated functions. Cell Rep. 2015; 11(2):210-9. DOI: 10.1016/j.celrep.2015.03.019. View

Wajner M, Amaral A . Mitochondrial dysfunction in fatty acid oxidation disorders: insights from human and animal studies. Biosci Rep. 2015; 36(1):e00281. PMC: 4718505. DOI: 10.1042/BSR20150240. View

Loughery J, Cox M, Smith L, Meek D . Critical role for p53-serine 15 phosphorylation in stimulating transactivation at p53-responsive promoters. Nucleic Acids Res. 2014; 42(12):7666-80. PMC: 4081099. DOI: 10.1093/nar/gku501. View

Pauklin S, Vallier L . The Cell-Cycle State of Stem Cells Determines Cell Fate Propensity. Cell. 2017; 156(6):1338. PMC: 5652229. DOI: 10.1016/j.cell.2014.02.044. View

Lee K, Green M . A cellular transcription factor E4F1 interacts with an E1a-inducible enhancer and mediates constitutive enhancer function in vitro. EMBO J. 1987; 6(5):1345-53. PMC: 553939. DOI: 10.1002/j.1460-2075.1987.tb02374.x. View

Helsel A, Oatley M, Oatley J . Glycolysis-Optimized Conditions Enhance Maintenance of Regenerative Integrity in Mouse Spermatogonial Stem Cells during Long-Term Culture. Stem Cell Reports. 2017; 8(5):1430-1441. PMC: 5425612. DOI: 10.1016/j.stemcr.2017.03.004. View

10.

Le Cam L, Lacroix M, Ciemerych M, Sardet C, Sicinski P . The E4F protein is required for mitotic progression during embryonic cell cycles. Mol Cell Biol. 2004; 24(14):6467-75. PMC: 434264. DOI: 10.1128/MCB.24.14.6467-6475.2004. View

11.

Hu C, Fan L, Cen P, Chen E, Jiang Z, Li L . Energy Metabolism Plays a Critical Role in Stem Cell Maintenance and Differentiation. Int J Mol Sci. 2016; 17(2):253. PMC: 4783982. DOI: 10.3390/ijms17020253. View

12.

Abe H, Alavattam K, Kato Y, Castrillon D, Pang Q, Andreassen P . CHEK1 coordinates DNA damage signaling and meiotic progression in the male germline of mice. Hum Mol Genet. 2018; 27(7):1136-1149. PMC: 6185175. DOI: 10.1093/hmg/ddy022. View

13.

Velte E, Niedenberger B, Serra N, Singh A, Roa-DeLaCruz L, Hermann B . Differential RA responsiveness directs formation of functionally distinct spermatogonial populations at the initiation of spermatogenesis in the mouse. Development. 2019; 146(12). PMC: 6602341. DOI: 10.1242/dev.173088. View

14.

Le Cam L, Linares L, Paul C, Julien E, Lacroix M, Hatchi E . E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation. Cell. 2006; 127(4):775-88. DOI: 10.1016/j.cell.2006.09.031. View

15.

de Rooij D . The nature and dynamics of spermatogonial stem cells. Development. 2017; 144(17):3022-3030. DOI: 10.1242/dev.146571. View

16.

Chagraoui J, Niessen S, Lessard J, Girard S, Coulombe P, Sauvageau M . E4F1: a novel candidate factor for mediating BMI1 function in primitive hematopoietic cells. Genes Dev. 2006; 20(15):2110-20. PMC: 1536061. DOI: 10.1101/gad.1453406. View

17.

Ehmcke J, Schlatt S . A revised model for spermatogonial expansion in man: lessons from non-human primates. Reproduction. 2006; 132(5):673-80. DOI: 10.1530/rep.1.01081. View

18.

Lacroix M, Rodier G, Kirsh O, Houles T, Delpech H, Seyran B . E4F1 controls a transcriptional program essential for pyruvate dehydrogenase activity. Proc Natl Acad Sci U S A. 2016; 113(39):10998-1003. PMC: 5047171. DOI: 10.1073/pnas.1602754113. View

19.

Luo J, Megee S, Dobrinski I . Asymmetric distribution of UCH-L1 in spermatogonia is associated with maintenance and differentiation of spermatogonial stem cells. J Cell Physiol. 2009; 220(2):460-8. PMC: 2732714. DOI: 10.1002/jcp.21789. View

20.

Yan R, Yang Q, Yang Q . E4 Transcription Factor 1 (E4F1) Regulates Sertoli Cell Proliferation and Fertility in Mice. Animals (Basel). 2020; 10(9). PMC: 7552733. DOI: 10.3390/ani10091691. View