Reorganized 3D Genome Structures Support Transcriptional Regulation in Mouse Spermatogenesis

Luo, Zhengyu; Wang, Xiaorong; Jiang, Hong; Wang, Ruoyu; Jian, Chen; Chen, Yu‐Sheng; Xu, Qianlan; Cao, Jun; Gong, Xiaohua; Wu, Ji; Yang, Yun‐Gui; Li, Wenbo; Han, Chunsheng; Cheng, C. Yan; Rosenfeld, Michael G.; Sun, Fei; Song, Xiaoyuan

doi:10.1016/j.isci.2020.101034

Cited by 42 publications

(61 citation statements)

References 66 publications

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“…6A). This proposal is congruent with previously reported over-representation of A-compartment regions along chromosomal axes [42,43], and aligns with the enrichment of meiotic cohesin peaks in A-compartment [17,18]. Transcriptionally active genomic regions with decondensed chromatin are furthermore associated with increased spatial accessibility [45,27]; together this may resolve the otherwise puzzling low cis/total ratio observed at meiotic cohesin ChIP-seq sites, which often overlap promoters.…”

Section: Discussionsupporting

confidence: 90%

“…Here we investigate how 3D genome folding relates to PRDM9 binding, DSBs, and crossover formation in mice. In particular, our work makes use of recent Hi-C datasets measuring the 3D conformation of meiotic chromosomes[14, 15, 16, 17, 18], and extends their findings on recombination[14]. Meiotic chromosomes adopt a brush-loop conformation characterized by chromatin loops attached to a central axis[19].…”

Section: Introductionmentioning

confidence: 94%

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Genome-wide variability in recombination activity is associated with meiotic chromatin organization

Jin

Fudenberg

Pollard

2021

Preprint

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BackgroundRecombination enables reciprocal exchange of genomic information between parental chromosomes and successful segregation of homologous chromosomes during meiosis. Errors in this process lead to negative health outcomes, while variability in recombination rate affects genome evolution. In mammals, most crossovers occur in hotspots defined by PRDM9 motifs, though PRDM9 binding sites are not all equally hot. We hypothesize that dynamic patterns of meiotic genome folding are linked to recombination activity.ResultsWe apply an integrative bioinformatics approach to analyze how three-dimensional (3D) chromosomal organization during meiosis relates to rates of double-strandbreak (DSB) and crossover formation at PRDM9 hotspots. We show that active, spatially accessible genomic regions during meiotic prophase are associated with DSB-favoured hotspots, which further adopt a transient locally active configuration in early prophase. Conversely, crossover formation is depleted among DSBs in spatially accessible regions during meiotic prophase, particularly within gene bodies. We also find evidence that active chromatin regions have smaller average loop sizes in mammalian meiosis. Collectively, these findings establish that differences in chromatin architecture along chromosomal axes are associated with variable recombination activity.ConclusionsWe propose an updated framework describing how 3D organization of brush-loop chromosomes during meiosis may modulate recombination.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 94%

Genome-wide variability in recombination activity is associated with meiotic chromatin organization

Jin

Fudenberg

Pollard

2021

Preprint

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“…The switch in gene expression programs could be facilitated by genome-wide changes leading to the de novo formation of accessible chromatin ( Maezawa et al, 2018 ), and the extensive reprogramming of chromatin 3D architecture that takes place in meiotic cells ( Alavattam et al, 2019 ; Patel et al, 2019 ; Vara et al, 2019 ; Wang et al, 2019 ; Luo et al, 2020 ). An integration of Hi-C (high-throughput genome-wide chromatin conformation capture) and RNA-seq from purified mouse spermatogenic cell populations, showed a switching in a subset of B (inactive) compartments to A (active) compartments in the chromatin of PS; the number of genome regions in A compartments was higher in PS, suggesting that PS chromatin is in a more transcriptionally active state.…”

Section: The Lag Between Transcription and Translationmentioning

confidence: 99%

Transcriptomics of Meiosis in the Male Mouse

Geisinger

Rodríguez-Casuriaga

Benavente

2021

Front. Cell Dev. Biol.

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Molecular studies of meiosis in mammals have been long relegated due to some intrinsic obstacles, namely the impossibility to reproduce the process in vitro, and the difficulty to obtain highly pure isolated cells of the different meiotic stages. In the recent years, some technical advances, from the improvement of flow cytometry sorting protocols to single-cell RNAseq, are enabling to profile the transcriptome and its fluctuations along the meiotic process. In this mini-review we will outline the diverse methodological approaches that have been employed, and some of the main findings that have started to arise from these studies. As for practical reasons most studies have been carried out in males, and mostly using mouse as a model, our focus will be on murine male meiosis, although also including specific comments about humans. Particularly, we will center on the controversy about gene expression during early meiotic prophase; the widespread existing gap between transcription and translation in meiotic cells; the expression patterns and potential roles of meiotic long non-coding RNAs; and the visualization of meiotic sex chromosome inactivation from the RNAseq perspective.

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“… F. Aggregated scATAC-seq profiles showing SE regions near Nanos2 with inferred TAD domains[72] and co-accessible CREs.…”

Section: Resultsmentioning

confidence: 99%

“…Accordingly, genes within high-density CCANs were strongly enriched in super-enhancer associated genes (p < 8.339e-09, hypergeometric test, representation factor = 1.5). Focusing on individual loci, we observed key EMT and spermatogonia related genes that exhibited patterns of coordinated regulation, which tended to occupy the same topologically associated domain (TAD) in spermatogonia [72] . We found super-enhancer regions located at Nanos2 and Tgfb1 loci.…”

Section: Gscmentioning

confidence: 99%

scATAC-Seq reveals epigenetic heterogeneity associated with an EMT-like process in male germline stem cells and its regulation by G9a

Liao

Suen

Luk

et al. 2020

Preprint

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Epithelial-mesenchymal transition (EMT) is a phenomenon in which epithelial cells acquire mesenchymal traits. It contributes to organogenesis and tissue homeostasis, as well as stem cell differentiation. Emerging evidence indicates that heterogeneous expression of EMT gene markers presents in sub-populations of germline stem cells (GSCs). However, the functional implications of such heterogeneity are largely elusive. Here, we unravelled an EMT-like process in GSCs by in vitro extracellular matrix (ECM) model and single-cell genomics approaches. Through modulating ECM, we demonstrated that GSCs exist in interconvertible epithelial-like and mesenchymal-like cell states. GSCs gained higher migratory ability after transition to a mesenchymal-like cell state, which was largely mediated by the TGF-β signaling pathway. Dynamics of epigenetic regulation at the single-cell level was also found to align with the EMT-like process. Chromatin accessibility profiles generated by single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) clustered GSCs into epithelial-like and mesenchymal-like states, which were associated with differentiation status. The high-resolution data revealed novel regulators in the EMT-like process, including transcription factors Zeb1 and Hes1. We further identified putative enhancer-promoter interactions and cis-co-accessibility networks at loci such as Tgfb1, Notch1 and Lin28a. Importantly, we demonstrated that histone methyltransferase G9a promoted the GSC EMT-like process in vitro and contributed to neonatal germ cell migration in vivo. Our work thus provides the foundation for understanding the EMT-like process and a comprehensive resource for future investigation of epigenetic regulatory networks in GSCs.

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Reorganized 3D Genome Structures Support Transcriptional Regulation in Mouse Spermatogenesis

Cited by 42 publications

References 66 publications

Genome-wide variability in recombination activity is associated with meiotic chromatin organization

Genome-wide variability in recombination activity is associated with meiotic chromatin organization

Transcriptomics of Meiosis in the Male Mouse

scATAC-Seq reveals epigenetic heterogeneity associated with an EMT-like process in male germline stem cells and its regulation by G9a

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