THESIS
2021
1 online resource (xiii, 143 pages) : illustrations (some color)
Abstract
Epigenetics regulation plays a critical role in determining cell identity by controlling
the accessibility of lineage-specific regulatory regions. In muscle stem cells, epigenetic
mechanisms of how chromatin accessibility is modulated during muscle stem cell quiescence
exit and lineage progression are not fully understood. Here, we identified a
long noncoding RNA, LncMyoD, which functions as a chromatin modulator for myogenic
lineage determination and progression. The depletion of LncMyoD in muscle
stem cells led to the downregulation of myogenic genes and defects in myogenic differentiation.
LncMyoD exclusively binds with MyoD and not other myogenic regulatory
factors and promotes transactivation of target genes. The mechanistic study revealed
that loss of LncMyoD prevents the establis...[
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Epigenetics regulation plays a critical role in determining cell identity by controlling
the accessibility of lineage-specific regulatory regions. In muscle stem cells, epigenetic
mechanisms of how chromatin accessibility is modulated during muscle stem cell quiescence
exit and lineage progression are not fully understood. Here, we identified a
long noncoding RNA, LncMyoD, which functions as a chromatin modulator for myogenic
lineage determination and progression. The depletion of LncMyoD in muscle
stem cells led to the downregulation of myogenic genes and defects in myogenic differentiation.
LncMyoD exclusively binds with MyoD and not other myogenic regulatory
factors and promotes transactivation of target genes. The mechanistic study revealed
that loss of LncMyoD prevents the establishment of a permissive chromatin environment at myogenic E-box-containing regions, therefore restricts the binding of MyoD.
Furthermore, the depletion of LncMyoD strongly impairs the reprogramming of fibroblasts
into the myogenic lineage. We further investigated the trajectory of chromatin
accessibility changes during muscle stem cell quiescence exit. The results showed that
the chromatin structure of muscle stem cells changes dramatically within the first 30
min after injury-induced activation and muscle stem cells establish the most accessible
chromatin at 4 hours post-injury. We also identified potential Pax7 enhancers which
may be involved in maintaining the quiescent state of muscle stem cells. Taken together,
our study showed the dramatic changes of chromatin accessibility during muscle stem
cells quiescence exit and lineage progression and found a MyoD-associated lncRNA,
LncMyoD, that promotes myogenic gene expression through modulating MyoD accessibility
to chromatin to regulate myogenic lineage determination and progression.
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