Multiscale 3D genome reorganization during skeletal muscle stem cell lineage progression and aging

Zhao, Yu; Ding, Yudan; He, Liangqiang; Qianneng, Zhou; Chen, Xiaona; Li, Yuying; Alfonsi, Maria Vittoria; Wu, Zhenguo; Sun, Hao; Wang, Huating

doi:10.1126/sciadv.abo1360

Cited by 23 publications

(29 citation statements)

References 84 publications

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“…Table S4). Next, we took a close examination of the Ccl5 locus and found no YY1 binding at its promoter region, instead, a binding site was identified at a distal site which was a potential enhancer by analyzing our previously published H3K27ac ChIP-seq data( 37 ) (Fig. 6F).…”

Section: Resultsmentioning

confidence: 99%

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Skeletal Muscle Stem Cells Modulate Niche Function in Duchenne Muscular Dystrophy through YY1-CCL5 Axis

Li,

Sun

et al. 2024

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Stem cell activity is known to be tightly regulated by both intrinsic and extrinsic pathways but less is known about whether and how stem cells modulate their niche microenvironment. Adult skeletal muscle stem cells (MuSCs) are indispensable for muscle regeneration and also tightly regulated by macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in the niche. Deregulated MuSC/MP/FAP interactions and the ensuing inflammation and fibrosis are hallmarks of dystrophic muscle. Here in this study we demonstrate that intrinsic deletion of transcription factor YY1 in MuSCs exacerbates dystrophic pathologies by altering the cellular composition and heterogeneity of MPs and FAPs. Further analysis reveals that the YY1 loss induces the expression of immune genes in MuSCs, including Ccl5. Augmented secretion of CCL5 from MuSCs promotes the recruitment of MPs via CCL5/CCR5 mediated crosstalk, which subsequently hinders the apoptosis and clearance of FAPs through elevated TGFβ1 accumulation. Maraviroc mediated pharmacological blockade of the CCL5/CCR5 axis effectively mitigates muscle dystrophy and improves muscle performance. Lastly, we further demonstrate that YY1 represses Ccl5 transcription in MuSCs by directly binding to its enhancer thus facilitating promoter-enhancer looping. Altogether, our study has demonstrated the previously unappreciated role of MuSCs in actively shaping their niche microenvironment through secreting immunomodulatory cytokines, and has also provided novel insight into the therapeutic intervention of muscle dystrophy.

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Section: Resultsmentioning

confidence: 99%

“…Data were analyzed by Hi-C Pro, juicer box software and mapping to mouse genome mm10. Raw Hi-C data were processed as previously described( 49, 64 ). Briefly, the in-situ Hi-C data was processed with a standard pipeline HiC-Pro ( 65 ).…”

Section: Methodsmentioning

confidence: 99%

Skeletal Muscle Stem Cells Modulate Niche Function in Duchenne Muscular Dystrophy through YY1-CCL5 Axis

Li,

Sun

et al. 2024

Preprint

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Section: Sox11 Expression Is Reduced With Age In Muscs Associated Wit...mentioning

confidence: 99%

“…Recent findings indicate that the 3D structure of the genome reorganizes and underpins the transcriptome remodeling during SC aging (74,75,76). Thus, we leveraged our recently published Hi-C datasets (74) to investigate the 3D organization around the Sox11 locus. In freshly isolated MuSCs (FISCs) from young mice, a prominent topologically associated domain (TAD) structure harboring Sox11 locus was observed, and it was largely maintained in aged FISCs (Fig.…”

Section: Sox11 Expression Is Reduced With Age In Muscs Associated Wit...mentioning

confidence: 99%

Sox11 is enriched in myogenic progenitors but dispensable for development and regeneration of skeletal muscle

Oprescu

Baumann

Chen

et al. 2023

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Transcription factors (TFs) play key roles in regulating the differentiation and function of stem cells, including muscle satellite cells (MuSCs), a resident stem cell population responsible for postnatal regeneration of the skeletal muscle. Sox11 belongs to the Sry-related HMG-box (SOX) family of TFs that play diverse roles in stem cell behavior and tissue specification. Analysis of single-cell RNA-sequencing (scRNA-seq) datasets identify a specific enrichment of Sox11 mRNA in differentiating but not quiescent MuSCs. Consistent with the scRNA-seq data, Sox11 levels increase during differentiation of murine primary myoblasts in vitro. scRNA-seq data comparing muscle regeneration in young and old mice further demonstrate that Sox11 expression is reduced in aged MuSCs. Age-related decline of Sox11 expression is associated with reduced chromatin contacts within the topologically associated domains. Unexpectedly, Myod1Cre-driven deletion of Sox11 in embryonic myoblasts has no effects on muscle development and growth, resulting in apparently healthy muscles that regenerate normally. Pax7CreER or Rosa26CreER driven (MuSC-specific or global) deletion of Sox11 in adult mice similarly has no effects on MuSC differentiation or muscle regeneration. These results identify Sox11 as a novel myogenic differentiation marker with reduced expression in quiescent and aged MuSCs, but the specific function of Sox11 in myogenesis remain to be elucidated.

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“…Following previous procedure [10], to separate the genome into A and B compartments, the ICE normalized intra-chromosomal interaction matrices at 100-kb resolution were transformed to observe/expect contact matrices, and the background (expected) contact matrices were generated to eliminate bias caused by distance-dependent decay of interaction frequency and read depth difference [42,59]. Pearson correlation was then applied to the transformed matrices and the first principal component (PC1) of these matrices was divided into two clusters.…”

Section: Identification and Analysis Of Compartments And Tadsmentioning

confidence: 99%

Pervasive RNA Binding Protein Enrichment on TAD Boundaries Regulates TAD Organization

Sun,

Zhou,

Qiao

et al. 2023

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Mammalian genome is hierarchically organized by CTCF and cohesin through loop extrusion mechanism to facilitate the organization of topologically associating domains (TADs). Mounting evidence suggests additional factors/mechanisms exist to orchestrate TAD formation and maintenance. In this study, we investigate the potential role of RNA binding proteins (RBPs) in TAD organization. By integrated analyses of global RBP binding and 3D genome mapping profiles from both K562 and HepG2 cells, our study unveils the prevalent enrichment of RBPs on TAD boundaries and define boundary associated RBPs (baRBPs). We also characterize chromatin features of baRBP binding and uncover clustering among baRBPs and with transcription factors (TFs). Moreover, we found that baRBP binding is correlated with enhanced TAD insulation strength and in a CTCF independent manner. Further analyses revealed that baRBP binding is associated with nascent promoter transcription thus RBP/transcription may synergistically demarcate TADs. Additional experimental testing was performed using RBFox2 as a paradigm. Knockdown ofRBFox2in K562 cells causes remarkable TAD reorganization and boundary loss. Moreover, we found RBFox2 enrichment on TAD boundaries is a conserved phenomenon in C2C12 myoblast (MB) cells. RBFox2 is down-regulated and its bound boundaries are remodeled during MB differentiation into myotubes (MTs). Knockout ofRbfox2in MBs also causes significant boundary reorganization. Finally, transcriptional inhibition in C2C12 cells indeed decreases RBFox2 binding and disrupts TAD boundary insulation. Altogether, our findings demonstrate that RBPs can play active role in modulating TAD organization through co-transcriptional association and synergistic action with nascent promoter transcripts.

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Multiscale 3D genome reorganization during skeletal muscle stem cell lineage progression and aging

Cited by 23 publications

References 84 publications

Skeletal Muscle Stem Cells Modulate Niche Function in Duchenne Muscular Dystrophy through YY1-CCL5 Axis

Skeletal Muscle Stem Cells Modulate Niche Function in Duchenne Muscular Dystrophy through YY1-CCL5 Axis

Sox11 is enriched in myogenic progenitors but dispensable for development and regeneration of skeletal muscle

Pervasive RNA Binding Protein Enrichment on TAD Boundaries Regulates TAD Organization

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