Hoxa10 is a functional positional memory that governs stem cell function in adult skeletal muscle
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ABSTRACT:
PROVIDER: PRJNA644944 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12179612_1.fastq.gz | Fastqsanger.gz | |||
| SRR12179612_2.fastq.gz | Fastqsanger.gz | |||
| SRR12179613_1.fastq.gz | Fastqsanger.gz | |||
| SRR12179613_2.fastq.gz | Fastqsanger.gz | |||
| SRR12179614_1.fastq.gz | Fastqsanger.gz |
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Project description:Skeletal muscle is the contractile tissue that distributes throughout body, with its functionally heterogeneous properties amongst muscles, which may relate to region specific pathology of muscle diseases. Here we found that homeobox (Hox) genes, key regulators of body-plan in the embryo, are region-specifically and robustly maintained as positional memory in both muscle and its associated stem cells named satellite cells in adult mice and humans. Although satellite cell function in adults was unaffected by genetic loss of Hoxa10 in muscle progenitors at the developmental stage, postnatal deletion of Hoxa10 in satellite cells led to genomic instability and mitosis abnormality, resulting in a remarkable decline in regenerative ability of muscles in a region-specific manner. Our results suggest that Hox-based positional memory is flexibly established during embryonic development and governs topographic function of stem cells in adult muscles once it is fixed, potentially influencing the region-specific weakness in muscle diseases
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Project description:Hoxa10 mediates positional memory to govern stem cell function in adult skeletal muscle
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Project description:Muscle stem cells (satellite cells) are distributed throughout the body and have heterogeneous properties among muscles. However, functional topographical genes in satellite cells of adult muscle remain unidentified. Here, we show that expression of Homeobox-A (Hox-A) cluster genes accompanied with DNA hypermethylation of the Hox-A locus was robustly maintained in both somite-derived muscles and their associated satellite cells in adult mice, which recapitulates their embryonic origin. Somite-derived satellite cells were clearly separated from cells derived from cranial mesoderm in Hoxa10 expression. Hoxa10 inactivation led to genomic instability and mitotic catastrophe in somite-derived satellite cells in mice and human. Satellite cell–specific Hoxa10 ablation in mice resulted in a decline in the regenerative ability of somite-derived muscles, which were unobserved in cranial mesoderm–derived muscles. Thus, our results show that Hox gene expression profiles instill the embryonic history in satellite cells as positional memory, potentially modulating region-specific pathophysiology in adult muscles.
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Project description:Skeletal muscle is contractile tissue distributed throughout the body with functionally heterogeneous properties that may relate to region-specific pathophysiology of muscle diseases. Recent studies revealed that muscle stem cells (satellite cells) are a functional heterogeneous population in different muscles, dependent not only on fiber-types but also on embryonic origin. Homeobox (Hox) genes are key regulators of the embryonic body plan. Here, we showed that Hox-A cluster genes are robustly maintained in adult muscles and their associated satellite cells of both mice and humans in a body region-specific manner, whose distribution almost recapitulates their embryonic origin. The region-specific expression of Hox genes was linked to DNA hypermethylation status of Hox-A locus. Importantly, Hox gene expression is a functional memory; Hoxa10 inactivation in satellite cells led to genomic instability and mitotic catastrophe, resulting in a decline in the regionally specific regenerative ability of muscles in mice, even though Hox paralogs are known to be often functionally redundant. Thus, our results demonstrate that the topographic Hox gene expression profile could be a geotagging molecular signature that reflects the anatomical location and embryonic history of resident muscle stem cells, potentially contributing to regionally specific regulations of adult skeletal muscles.
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