scholarly journals HIRA stabilizes skeletal muscle lineage identity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joana Esteves de Lima ◽  
Reem Bou Akar ◽  
Léo Machado ◽  
Yuefeng Li ◽  
Bernadette Drayton-Libotte ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Lineage ◽  
Promoter Regions ◽  
Cell Fates ◽  
Regulatory Regions ◽  
Muscle Stem Cells ◽  
Adult Mice ◽  
H3k4me3 Mark ◽  
Muscle Genes ◽  
Muscle Gene

AbstractThe epigenetic mechanisms coordinating the maintenance of adult cellular lineages and the inhibition of alternative cell fates remain poorly understood. Here we show that targeted ablation of the histone chaperone HIRA in myogenic cells leads to extensive transcriptional modifications, consistent with a role in maintaining skeletal muscle cellular identity. We demonstrate that conditional ablation of HIRA in muscle stem cells of adult mice compromises their capacity to regenerate and self-renew, leading to tissue repair failure. Chromatin analysis of Hira-deficient cells show a significant reduction of histone variant H3.3 deposition and H3K27ac modification at regulatory regions of muscle genes. Additionally, we find that genes from alternative lineages are ectopically expressed in Hira-mutant cells via MLL1/MLL2-mediated increase of H3K4me3 mark at silent promoter regions. Therefore, we conclude that HIRA sustains the chromatin landscape governing muscle cell lineage identity via incorporation of H3.3 at muscle gene regulatory regions, while preventing the expression of alternative lineage genes.

scholarly journals Epigenetic regulation of Wnt7b expression by the cis-acting long noncoding RNA lnc-Rewind in muscle stem cells

2020 ◽  
Author(s):  
Andrea Cipriano ◽  
Martina Macino ◽  
Giulia Buonaiuto ◽  
Tiziana Santini ◽  
Beatrice Biferali ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Epigenetic Regulation ◽  
Noncoding Rna ◽  
Muscle Stem Cells ◽  
Cis Acting ◽  
Adult Muscle ◽  
Histone Lysine Methyltransferase ◽  
Muscle Genes ◽  
Muscle Homeostasis

ABSTRACTSkeletal muscle possesses an outstanding capacity to regenerate upon injury due to the adult muscle stem cells (MuSCs) activity. This ability requires the proper balance between MuSCs expansion and differentiation which is critical for muscle homeostasis and contributes, if deregulated, to muscle diseases. Here, we functionally characterize a novel chromatin-associated lncRNA, lnc-Rewind, which is expressed in murine MuSCs and conserved in human. We find that, in mouse, lnc-Rewind acts as an epigenetic regulator of MuSCs proliferation and expansion by influencing the expression of skeletal muscle genes and several components of the WNT (Wingless-INT) signalling pathway. Among them, we identified the nearby Wnt7b gene as a direct lnc-Rewind target. We show that lnc-Rewind interacts with the G9a histone lysine methyltransferase and mediates the in cis repression of Wnt7b by H3K9me2 deposition. Overall, these findings provide novel insights into the epigenetic regulation of adult muscle stem cells fate by lncRNAs.

scholarly journals Myogenin is required for assembly of the transcription machinery on muscle genes during skeletal muscle differentiation

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245618
Author(s):  
Abhinav Adhikari ◽  
William Kim ◽  
Judith Davie
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Gene Activation ◽  
Gene Promoters ◽  
Muscle Gene Expression ◽  
Transcription Machinery ◽  
Muscle Genes ◽  
Muscle Gene

Skeletal muscle gene expression is governed by the myogenic regulatory family (MRF) which includes MyoD (MYOD1) and myogenin (MYOG). MYOD1 and MYOG are known to regulate an overlapping set of muscle genes, but MYOD1 cannot compensate for the absence of MYOG in vivo. In vitro, late muscle genes have been shown to be bound by both factors, but require MYOG for activation. The molecular basis for this requirement was unclear. We show here that MYOG is required for the recruitment of TBP and RNAPII to muscle gene promoters, indicating that MYOG is essential in assembling the transcription machinery. Genes regulated by MYOD1 and MYOG include genes required for muscle fusion, myomaker and myomerger, and we show that myomaker is fully dependent on activation by MYOG. We also sought to determine the role of MYOD1 in MYOG dependent gene activation and unexpectedly found that MYOG is required to maintain Myod1 expression. However, we also found that exogenous MYOD1 was unable to compensate for the loss of Myog and activate muscle gene expression. Thus, our results show that MYOD1 and MYOG act in a feed forward loop to maintain each other’s expression and also show that it is MYOG, and not MYOD1, that is required to load TBP and activate gene expression on late muscle gene promoters bound by both factors.

scholarly journals Epigenetic regulation of Wnt7b expression by the cis-acting long noncoding RNA Lnc-Rewind in muscle stem cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Andrea Cipriano ◽  
Martina Macino ◽  
Giulia Buonaiuto ◽  
Tiziana Santini ◽  
Beatrice Biferali ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Epigenetic Regulation ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Muscle Stem Cells ◽  
Cis Acting ◽  
Adult Muscle ◽  
Histone Lysine Methyltransferase ◽  
Muscle Genes

Skeletal muscle possesses an outstanding capacity to regenerate upon injury due to the adult muscle stem cell (MuSC) activity. This ability requires the proper balance between MuSC expansion and differentiation, which is critical for muscle homeostasis and contributes, if deregulated, to muscle diseases. Here, we functionally characterize a novel chromatin-associated long noncoding RNA (lncRNA), Lnc-Rewind, which is expressed in murine MuSCs and conserved in human. We find that, in mouse, Lnc-Rewind acts as an epigenetic regulator of MuSC proliferation and expansion by influencing the expression of skeletal muscle genes and several components of the WNT (Wingless-INT) signalling pathway. Among them, we identified the nearby Wnt7b gene as a direct Lnc-Rewind target. We show that Lnc-Rewind interacts with the G9a histone lysine methyltransferase and mediates the in cis repression of Wnt7b by H3K9me2 deposition. Overall, these findings provide novel insights into the epigenetic regulation of adult muscle stem cells fate by lncRNAs.

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