TAF4b transcription networks regulating early oocyte differentiation

Abstract

Establishment of a healthy ovarian reserve is contingent upon numerous regulatory pathways during embryogenesis. Previously, mice lacking TBP-associated factor 4b (Taf4b) were shown to exhibit a diminished ovarian reserve. However, potential oocyte-intrinsic functions of TAF4b have not been examined. Here we use a combination of gene expression profiling and chromatin mapping to characterize TAF4b-dependent gene regulatory networks in mouse oocytes. We find that Taf4b-deficient oocytes display inappropriate expression of meiotic, chromatin, and X-linked genes. Furthermore, dysregulated genes in Taf4b-deficient oocytes exhibit an unexpected amount of overlap with dysregulated genes in Turner Syndrome oocytes. Using Cleavage Under Targets and Release Using Nuclease (CUT&RUN), we observed TAF4b enrichment at genes involved in chromatin remodeling and DNA repair, some of which are differentially expressed in Taf4b-deficient oocytes. Interestingly, TAF4b target genes were enriched for Sp/Klf family and NFY target motifs rather than TATA-box motifs, suggesting an alternate mode of promoter interaction. Together, our data connects several gene regulatory nodes that contribute to the precise development of the mammalian ovarian reserve.

TAF4b Transcriptional Regulation During Cellular Quiescence of Developing Prospermatogonia

“…Distinctive GO categories from the CUT&RUN included RNA processing, chromatin modification, and cell cycle regulation. The most consistent DNA motifs within the TAF4b-bound promoters included Sp/Klf family and NFY binding sites; a remarkable similarity to our findings in embryonic mouse oocytes, and for the first time linking these ubiquitous factors to the regulation of ProSpg transcription [24]. Finally, we compared our male embryonic germ cell data with our recently reported TAF4b genomic analyses of female embryonic germ cells revealing several core and sex-specific cellular processes regulated by TAF4b.…”

“…Our work indicates that TAF4b performs essential developmental functions in spermatogenesis and oogenesis. We thus compared our findings in E16.5 male ProSpg (from this study) to E16.5 oocytes [24]. We plotted all our samples in one PCA plot and observed that the samples separated Accordingly, we conclude from all of these data that TAF4b regulates both sex-independent and sex-dependent embryonic germ cell development further highlighting its critical transcription functions regulating male and female mammalian fertility.…”

“…This interestingly suggests that the E16.5 Taf4b -deficient ProSpg may have more similarities to E14.5 ProSpg than wildtype or heterozygous have to E14.5 ProSpg. Due to significant X chromosome expression effects we observed in Taf4b -deficient E16.5 female germ cells [24], we examined key aspects of X chromosome dosage to see if similar effects were occurring in Taf4b -deficient male germ cells. We investigated if there was a significant difference in autosomal expression compared to X chromosome expression, the X:A ratio, and the relative X expression (RXE) in E14.5 and E16.5 male germ cells ( Fig S3 ).…”

“…We investigated if there was a significant difference in autosomal expression compared to X chromosome expression, the X:A ratio, and the relative X expression (RXE) in E14.5 and E16.5 male germ cells ( Fig S3 ). No significant difference in any calculation was observed, suggesting that these significant X chromosome effects are unique to Taf4b -deficient female germ cells [24].…”

“…While we focus here on TAF4b's role in promoting the early development of the male germline, we have recently reported that at similar embryonic time points in development, TAF4b plays a critical role in early oocyte differentiation [24]. As female and male embryonic germ cells express unique sets of genes and navigate different biological processes, i.e., meiotic initiation vs. mitotic arrest, it is surprising that the same transcription factor would have distinct functions in the early life of these future gametes.…”