Integrative Genomic Analysis of In Vivo Muscle Regeneration After Severe Trauma
MIT Lincoln Laboratory Lexington United States
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Adult skeletal muscle is the dominant system through which complex physical actionsare accomplished and is uniquely capable of repair and regeneration after different types of insultor injury via resident stem cells. The in-vivo epigenomic and transcriptional mechanisms through which skeletal muscle repairs itself are partly understood and herein, we administer severe muscle trauma to a mouse tibialis anterior muscle and monitor the in-vivo dynamics of three histone modifications and gene expression across nine time points after injury. Integrating the genome-wide datasets, we show extensive chromatin state remodeling at cis-regulatory elements and observe the cooperative activity of lineage-specific transcription factors during progressions through different stages of healing. We highlight how one of the major regenerative programs IGF and PI3K signaling activated after injury is titrated by negative regulators temporally on multiple levels. Lastly, we illustrate the dynamics of non-coding RNAs during various stages after trauma, most notably during the switch from my oblast proliferation towards differentiation and eventual muscle regeneration. These results provide an unbiased, comprehensive view of the central factors that regulate muscle regeneration after severe trauma and underscore the multiple levels through which both local and global genetic and epigenetic patterns are regulated to enact appropriate and timely repair and regeneration.
- Medicine and Medical Research