EWSR1 affects PRDM9-dependent histone 3 methylation and provides a link between recombination hotspots and the chromosome axis protein REC8

Tian, Hui; Billings, Timothy; Petkov, Petko M.

doi:10.1091/mbc.e20-09-0604

Cited by 13 publications

(26 citation statements)

References 84 publications

(152 reference statements)

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“…We have reported that, during spermatogenesis, EWSR1 is one of the key regulators of meiotic recombination, by interacting with recombination hotspot determinator PRDM9 and meiotic-specific cohesin REC8 in leptotene and zygotene spermatocytes (Parvanov et al, 2017;Tian et al, 2021). Furthermore, although neither we nor others detected a function of EWSR1 in regulating gene expression or RNA binding during these prophase I stages, some of our findings indicated that EWSR1 may be involved in post-meiotic differentiation.…”

Section: Introductioncontrasting

confidence: 77%

“…To achieve this goal, we created an Ewsr1 pachytene stage-specific knockout mouse model, allowing us to separate its functions during late meiotic prophase I and spermatozoa maturation from those in early meiosis that we have already described (Tian et al, 2021). We now show that loss of EWSR1 at this stage does not affect proper meiosis completion, but that developing germ cells exhibit defects in spermatid elongation and chromocenter formation.…”

Section: Introductionmentioning

confidence: 91%

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Mouse EWSR1 is crucial for spermatid post-meiotic transcription and spermiogenesis

Tian

Petkov

2021

Development

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Spermatogenesis is precisely controlled by complex gene-expression programs. During mammalian male germ-cell development, a crucial feature is the repression of transcription before spermatid elongation. Previously, we discovered that the RNA-binding protein EWSR1 plays an important role in meiotic recombination in mouse, and showed that EWSR1 is highly expressed in late meiotic cells and post-meiotic cells. Here, we used an Ewsr1 pachytene stage-specific knockout mouse model to study the roles of Ewsr1 in late meiotic prophase I and in spermatozoa maturation. We show that loss of EWSR1 in late meiotic prophase I does not affect proper meiosis completion, but does result in defective spermatid elongation and chromocenter formation in the developing germ cells. As a result, male mice lacking EWSR1 after pachynema are sterile. We found that in Ewsr1 CKO round spermatids, transition from a meiotic gene-expression program to a post-meiotic and spermatid gene expression program related to DNA condensation is impaired, suggesting that EWSR1 plays an important role in regulation of spermiogenesis-related mRNA synthesis necessary for spermatid differentiation into mature sperm.

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Section: Introductioncontrasting

confidence: 77%

Section: Introductionmentioning

confidence: 91%

Mouse EWSR1 is crucial for spermatid post-meiotic transcription and spermiogenesis

Tian

Petkov

2021

Development

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“…The KRAB domain binds proteins that help to open local chromatin (P arvanov et al . 2017; T ian et al . 2021).…”

Section: Discussionmentioning

confidence: 99%

“…2019). The RNA-binding protein EWSR1 (T ian et al . 2021) and the chromatin remodeling factor HELLS (S pruce et al .…”

Section: Discussionmentioning

confidence: 99%

Differential effects of two catalytic mutations on full-length PRDM9 and its isolated PR/SET domain reveal a case of pseudo-modularity

Powers

Billings

Paigen

et al. 2021

Preprint

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PRDM9 is a DNA-binding histone methyltransferase that designates and activates recombination hotspots in mammals by locally trimethylating lysines 4 and 36 of histone H3. In mice, we recently reported two independently produced point mutations at the same residue, glu360pro (Prdm9EP) and glu360lys (Prdm9EK), which severely reduce its H3K4 and H3K36 methyltransferase activities in vivo. Prdm9EP is slightly less hypomorphic than Prdm9EK, but both mutations reduce both the number and amplitude of PRDM9-dependent H3K4me3 and H3K36me3 peaks in spermatocytes. While both mutations cause infertility with complete meiotic arrest in males, Prdm9EP, but not Prdm9EK, is compatible with some female fertility. When we tested the effects of these mutations in vitro, both Prdm9EP and Prdm9EK abolished H3K4 and H3K36 methyltransferase activity in full-length PRDM9. However, in the isolated PRDM9 PR/SET domain, these mutations selectively compromised H3K36 methyltransferase activity, while leaving H3K4 methyltransferase activity intact. The difference in these effects on the PR/SET domain versus the full-length protein show that PRDM9 is not an intrinsically modular enzyme; its catalytic domain is influenced by its tertiary structure and possibly by its interactions with DNA and other proteins in vivo. These two informative mutations illuminate the enzymatic chemistry of PRDM9, and potentially of PR/SET domains in general, reveal the minimal threshold of PRDM9-dependent catalytic activity for female fertility, and potentially have some practical utility for genetic mapping and genomics.

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“…Thus, the attachment of PRDM9 to chromosome axes may stabilize the entire complex and eventually allow efficient H3K4/K36 trimethylation. 21 …”

Section: From H3k4me3 To Dsbs: the Regulation Of Hotspotsmentioning

confidence: 99%

The molecular control of meiotic double-strand break (DSB) formation and its significance in human infertility

Jiang

et al. 2021

Asian J Androl

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EWSR1 affects PRDM9-dependent histone 3 methylation and provides a link between recombination hotspots and the chromosome axis protein REC8

Cited by 13 publications

References 84 publications

Mouse EWSR1 is crucial for spermatid post-meiotic transcription and spermiogenesis

Mouse EWSR1 is crucial for spermatid post-meiotic transcription and spermiogenesis

Differential effects of two catalytic mutations on full-length PRDM9 and its isolated PR/SET domain reveal a case of pseudo-modularity

The molecular control of meiotic double-strand break (DSB) formation and its significance in human infertility

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