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Transcription factor-like 5 is a potential DNA/RNA binding protein essential for maintaining male fertility in mice

ABSTRACT: Tissue-specific transcriptional factors often play key roles in the development of specific cell lineages. Transcription factor-like 5 (TCFL5) is a testis-specific protein that contains the basic helix-loop-helix domain but the in vivo functions of TCFL5 remained unknown. Here, we generated CRISPR/Cas9-mediated knockout mice to dissect the function of TCFL5 in mouse testes.The target RNAs of TCFL5 in wild-type mouse testes were analyzed by eCLIP-sequencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE187385 | GEO | 2022/01/17

REPOSITORIES: GEO

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Project description:In the mammalian testis, the pool of spermatogonia is amplified by mitosis before these progenitor germ cells undergo meiosis to generate the haploid cells that give rise to sperm. Extensive changes in the transcriptome accompany the onset of the pachytene stage of meiosis, including the transcriptional activation of meiotic genes, the pachytene piRNA pathway, as well as mRNAs required later during spermiogenesis. How transcription is regulated to ensure the precise timing of this major reprogramming of gene expression remains largely uncharacterized. Here, we report that the testis-specific transcription factor TCFL5 is initially activated by the transcription factor A-MYB during meiosis. Subsequently, A-MYB and TCFL5 mutually reinforce their own transcription establishing a central regulatory circuit that regulates meiosis and spermiogenesis, as well as mediates pachytene piRNA production. TCFL5 drives the transcription of 476 genes required for meiosis including genes encoding pachytene piRNA biogenesis proteins, and 796 genes required for spermiogenesis. Tcfl5−/− mutant mice are sterile and spermatogenesis arrests at the mid- or late-pachytene stage of meiosis. Intriguingly, Tcfl5 haploinsufficiency leads to reduced male fertility suggesting germ cells are sensitive to Tcfl5 dosage to develop. Compromised TCFL5 expression underlies the reduced fertility phenotype directly or indirectly through regulating other transcription factors in Tcfl5+/− mutant mice. TCFL5 drives the transcription of evolutionarily younger pachytene piRNAs, while A-MYB regulates older pachytene piRNAs. Older and younger piRNAs mutually initiate their own processing providing evidence how these selfish genetic elements hijack meiotic transcriptional network to amplify themselves. We also demonstrate that TCFL5-mediated regulation of male meiosis and piRNA production is conserved in macaque. Our data establish a direct role of TCFL5 in ensuring the simultaneous activation of genes required for meiosis and spermiogenesis in mammals.

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Transcription factor-like 5 is a potential DNA/RNA binding protein essential for maintaining male fertility in mice

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