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Multi-omics analysis reveals single-cell meiotic hotspot dynamics and epigenomic regulations in female mammals

ABSTRACT: Meiotic recombination initiates via DNA double-strand breaks (DSBs) at specialized hotspots, while the regulation of meiotic recombination hotspots in females remain elusive due to the scarcity of embryonic stage germ cells (EGCs). Here, we mapped genome-wide active recombination hotspots and estimated their activities in female EGCs at single-cell resolution, revealing the high variability in hotspot usage frequency among individual germ cells. Further investigation of nucleosome positioning and histone modifications at recombination hotspots revealed that PRDM9-mediated open chromatin and flanking H3K4me3 established earlier at high-frequency hotspots compared with less frequently used ones. Unexpectedly, although recombination hotspots usually distributed outside of heterochromatin, H3K9me3 was clearly enriched around hotspots in females, forming a unique H3K4me3/H3K9me3 bivalent state. And we showed that appropriate H3K9me3 level may be required for downstream DSB repairs. Together, our results provided novel understanding about the landscape and epigenomic regulation of recombination hotspots in females.

ORGANISM(S): Mus musculus

PROVIDER: GSE226475 | GEO | 2025/07/08

REPOSITORIES: GEO

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Project description:During mouse development, embryonic stage germ cells (EGCs) make crucial fate decisions, with female ones embark on meiosis whereas male ones enter mitotic arrest until birth. Despite the mounting knowledge about their reprogramming of epigenetic modifications, the dynamics of 3D genome structures within individual EGCs remains elusive. Herein, we presented a single-cell-input long-read Hi-C method, scNanoHi-C2, and systematically dissected the reprogramming dynamics of EGC chromatin structures. We found that, despite the similar attenuation of A/B compartments and topologically associating domains (TADs), and the appearance of refined A/B compartments in autosomes comparable to spermatogenesis, the X chromosomes of female EGCs showed enhanced specific interactions between B compartments probably due to their incomplete reactivation. By reconstructing single-cell 3D genome models, we revealed the dynamic chromosome positioning during meiosis at single-cell level, showing that the neighborhood between non-homologous chromosomes of EGCs was relatively random. At the same time, the transposable elements (TEs) underwent dramatic chromatin reorganization, and a preferential asymmetric distribution of Alu/B2 elements around the meiotic TAD boundaries emerged, which reflected the formation of refined-compartments, maintaining the balances between global chromatin condensation and local meiotic-specific transcription. Notably, we demonstrated the specific chromatin loop extrusion around recombination hotspots during meiosis, which may provide a structural basis facilitating reliable homologous recombination. We also revealed an unexpected chromatin structure in mitotic arrested male EGCs distinct from the previously assumed G0 status, which may prime the unique genome structure for subsequent spermatogenesis. Altogether, our study revealed key features of the chromatin structure reprogramming in EGCs, emphasizing the potential roles of 3D genome structures for mammalian germ cell development.

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Multi-omics analysis reveals single-cell meiotic hotspot dynamics and epigenomic regulations in female mammals

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