The histone modification reader ZCWPW1 is required for meiosis prophase I in male but not in female mice

Li, Miao; Huang, Tao; Li, Mengjing; Zhang, Chuanxin; Yu, Xiaochen; Yin, Yingying; Liu, Chao; Wang, Xin; Feng, Haiwei; Zhang, Tuo; Lin, Li; Han, Chunsheng; Lü, Gang; Li, Wei; Ma, Jinlong; Chen, Zi‐Jiang; Liu, Hongbin; Liu, Kui

doi:10.1126/sciadv.aax1101

Cited by 50 publications

(55 citation statements)

References 54 publications

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“…Hematoxylin Eosin (H&E) staining of tissue sections demonstrated the total absence of spermatids in the seminiferous tubules of Zcwpw1 KO/KO mice testes ( Figures 5A and S5C). Double immunofluorescence staining of chromosome spreads from spermatocytes with the SC axial element marker SYCP3 and the SC central element marker SYCP1 revealed Zcwpw1 KO/KO mice display partial chromosomal asynapsis and arrest at pachytene-like stage of prophase I ( Figure 5B), consistent with a recent report (Li et al, 2019a).…”

Section: Zcwpw1 Chromatin Occupancy Is Determined By Prdm9 In Allele supporting

confidence: 91%

“…Zcwpw1 is necessary for fertility in male mice, as Zcwpw1 KO/KO mice are azoospermic, similar to Prdm9 KO/KO . In contrast, Zcwpw1 KO females are initially fertile, but suffer from ovarian insufficiency as they age, likely due to delayed meiosis in fetal ovaries (Li et al, 2019a). This is also in contrast to Prdm9 KO females, which are completely infertile (Hayashi et al, 2005).…”

Section: Discussionmentioning

confidence: 92%

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Dual Histone Methyl Reader ZCWPW1 Facilitates Repair of Meiotic Double Strand Breaks

Mahgoub

Paiano

Bruno

et al. 2019

Preprint

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Meiotic crossovers result from homology-directed repair of double strand breaks (DSBs). Unlike yeast and plants, where DSBs are generated near gene promoters, in many vertebrates, DSBs are enriched at hotspots determined by the DNA binding activity of the rapidly evolving zinc finger array of PRDM9 (PR domain zinc finger protein 9). PRDM9 subsequently catalyzes trimethylation of lysine 4 and lysine 36 of Histone H3 in nearby nucleosomes. Here, we identify the dual histone methylation reader ZCWPW1, which is tightly co-expressed during spermatogenesis with Prdm9 and co-evolved with Prdm9 in vertebrates, as an essential meiotic recombination factor required for efficient synapsis and repair of PRDM9-dependent DSBs. In sum, our results indicate that the evolution of a dual histone methylation writer/reader system in vertebrates facilitated a shift in genetic recombination away from a static pattern near genes towards a flexible pattern controlled by the rapidly evolving DNA binding activity of PRDM9.

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Section: Zcwpw1 Chromatin Occupancy Is Determined By Prdm9 In Allele supporting

confidence: 91%

Section: Discussionmentioning

confidence: 92%

Dual Histone Methyl Reader ZCWPW1 Facilitates Repair of Meiotic Double Strand Breaks

Mahgoub

Paiano

Bruno

et al. 2019

Preprint

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“…To investigate the role of ZCWPW1 during meiosis in vivo, we produced an antibody against the full-length recombinant mouse protein ( Supplementary Figure 2) and studied the phenotype of a newly generated knockout (KO) mouse line for Zcwpw1, with a particular focus on fertility and meiotic recombination. In testes from wild-type (WT) mice, we observe a dynamic localisation of ZCWPW1 protein (Figure 2), similar but non-identical to that reported in a recent study (M. Li et al, 2019). ZCWPW1 shows a strong, punctate nuclear staining excluding the pericentromeric regions (clustered into chromocenters brightly stained with DAPI) in zygotene and early pachytene cells; we detected transcript expression in earlier pre-leptotene to leptotene cells (Jung et al, 2019).…”

Section: Zcwpw1 -/Micesupporting

confidence: 88%

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

Wells

Bitoun

Moralli

et al. 2019

Preprint

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During meiosis, homologous chromosomes pair (synapse) and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, recombination initiates with double-strand breaks (DSBs) within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have yet been identified.We identified Zcwpw1, which possesses H3K4me3 and H3K36me3 recognition domains, as highly co-expressed with Prdm9. Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognizes CpG dinucleotides, including within many Alu transposons.Male Zcwpw1 homozygous knockout mice show completely normal DSB positioning, but persistent DMC1 foci at many hotspots, particularly those more strongly bound by PRDM9, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest a model where ZCWPW1 recognition of PRDM9-bound sites on either the homologous, or broken, chromosome is critical for synapsis, and hence fertility. Graphical Abstract LegendIn humans and other species, recombination is initiated by double strand breaks at sites bound by PRDM9. Upon binding, PRDM9 deposits the histone marks H3K4me3 and H3K36me, but the functional importance of these marks has remained unknown. Here, we show that PRDM9 recruits ZCWPW1, a reader of both these marks, to its binding sites genome-wide. ZCWPW1 does not help position the breaks themselves, but is essential for their downstream repair and chromosome pairing, and ultimately meiotic success and fertility in mice.

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“…It is possible that this unique combination of histone modifications provides an epigenomic addressing system for recruiting downstream DSBs and recombination factors to hotspots. One putative hotspot epigenomic reader could be ZCWPW1, which has domains predicted to bind H3K4me3 and H3K36me3 and is required for meiotic progression in males (Jung et al, 2019;Li et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

Spruce

Dlamini

Ananda

et al. 2019

Preprint

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Chromatin barriers prevent spurious interactions between regulatory elements and DNAbinding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hotspots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hotspots and provide access for the DNA double-strand break (DSB) machinery. Recombination hotspots are decorated by a unique combination of histone modifications, not found at other regulatory elements. HELLS is recruited to hotspots by PRDM9, and is necessary for both histone modifications and DNA accessibility at hotspots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hotspot activation where HELLS and PRDM9 function as a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs.

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The histone modification reader ZCWPW1 is required for meiosis prophase I in male but not in female mice

Cited by 50 publications

References 54 publications

Dual Histone Methyl Reader ZCWPW1 Facilitates Repair of Meiotic Double Strand Breaks

Dual Histone Methyl Reader ZCWPW1 Facilitates Repair of Meiotic Double Strand Breaks

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

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