Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires Hes1 to bind diverse DNA sites

Noguchi, Yu Taro; Nakamura, Miki; Hino, Nobumasa; Nogami, Jumpei; Tsuji, Sayaka; Sato, Takahiko; Zhang, Lidan; Tsujikawa, Kazutake; Tanaka, Toru; Izawa, Kohei; Okada, Yoshiaki; Doi, Takefumi; Kokubo, Hiroki; Harada, Akihito; Uezumi, Akiyoshi; Gessler, Manfred; Ohkawa, Yasuyuki; Fukada, So Ichiro

doi:10.1242/dev.163618

Cited by 38 publications

(44 citation statements)

References 52 publications

(80 reference statements)

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“…We found that MyoD and MyoG are crucial TFs for myogenic differentiation, especially through regulation of Mef2c and Heyl (Figure 4D), which were also previously shown to provide key contributions to myogenic differentiation 36‐38 . We thus developed a correlation network between these four TFs and 149 of their correlated DE lncRNAs to improve our understanding of the function of lncRNAs (Figure 4E, Figure ).…”

Section: Resultssupporting

confidence: 55%

LncRNAs are regulated by chromatin states and affect the skeletal muscle cell differentiation

Xiang

et al. 2020

Cell Proliferation

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Objective This study aims to clarify the mechanisms underlying transcriptional regulation and regulatory roles of lncRNAs in skeletal muscle cell differentiation. Methods We analysed the expression patterns of lncRNAs via time‐course RNA‐seq. Then, we further combined the ATAC‐seq and ChIP‐seq to investigate the governing mechanisms of transcriptional regulation of differentially expressed (DE) lncRNAs. Weighted correlation network analysis and GO analysis were conducted to identify the transcription factor (TF)‐lncRNA pairs related to skeletal muscle cell differentiation. Results We identified 385 DE lncRNAs during C2C12 differentiation, the transcription of which is determined by chromatin states around their transcriptional start sites. The TF‐lncRNA correlation network showed substantially concordant changes in DE lncRNAs between C2C12 differentiation and satellite cell rapid growth stages. Moreover, the up‐regulated lncRNAs showed a significant decrease following the differentiation capacity of satellite cells, which gradually declines during skeletal muscle development. Notably, inhibition of the lncRNA Atcayos and Trp53cor1 led to the delayed differentiation of satellite cells. Those lncRNAs were significantly up‐regulated during the rapid growth stage of satellite cells (4‐6 weeks) and down‐regulated with reduced differentiation capacity (8‐12 weeks). It confirms that these lncRNAs are positively associated with myogenic differentiation of satellite cells during skeletal muscle development. Conclusions This study extends the understanding of mechanisms governing transcriptional regulation of lncRNAs and provides a foundation for exploring their functions in skeletal muscle cell differentiation.

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Section: Resultssupporting

confidence: 55%

LncRNAs are regulated by chromatin states and affect the skeletal muscle cell differentiation

Xiang

et al. 2020

Cell Proliferation

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“…The Pax7 CreERT2(Fan)/+ regeneration phenotype is consistent with previous findings (Mademtzoglou et al, 2018) and likely related to expression of only one Pax7 allele after CreERT2 insertion (Lepper et al, 2009). Leaky Cre recombinase activation and downregulation of Hey1, which is required to maintain satellite cells, in Pax7 CreERT2(Fan)/+ mice not treated with tamoxifen (Noguchi et al, 2019) could affect satellite cells during muscle regeneration.…”

Section: Discussionsupporting

confidence: 88%

Androgen receptor in satellite cells is not essential for muscle regenerations

et al. 2020

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The anabolic effects of androgen on skeletal muscles are thought to be mediated by androgen receptor (AR). Although multiple studies concerning the effects of AR in males have been performed, the molecular mechanisms of AR in skeletal muscles remain unclear. Here we first confirmed that satellite cells from mouse hindlimb muscles express AR. We then generated satellite cell-specific AR knockout mice using Pax7CreERT2 and ARL2/Y mice to test whether AR in satellite cells is necessary for muscle regeneration. Surprisingly, we found that muscle regeneration was compromised in both Pax7CreERT2(Fan)/+ control mice and Pax7CreERT2(Fan)/+;ARL2/Y mice compared to ARL2/Y mice. However, Pax7CreERT2(Gaka)/+;ARL2/Y;R26tdTomato/+ mice showed no significant differences between control and mutant muscle regeneration. These findings indicate that AR in satellite cells is not essential for muscle regeneration. We propose that Pax7CreERT2(Fan)/+ control mice should be included in all experiments, because these mice negatively affect the muscle regeneration and show the mild regeneration phenotype.

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“…Therefore, we hypothesized that canonical Notch signaling is responsible for MyoD suppression in proliferating MuSCs in overloaded muscle. Hey1 , Heyl, and Hes1 are crucial primary targets of canonical Notch signaling in MuSCs (Fukada et al, 2011; Lahmann et al, 2019) and function to suppress myogenic differentiation as Hey–Hes1 heterodimer complexes (Noguchi et al, 2019). Moreover, Hey1 and Heyl are both expressed in quiescent MuSCs, although their expression is drastically reduced during injury induced MuSC activation (Figure 3—figure supplement 1) (Fukada et al, 2011; Mourikis et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

“…Recently, Lahmann et al indicated that Hes1 controls oscillatory Myod expression in activated/proliferating MuSCs (Lahmann et al, 2019). We previously reported that neither Hey1 (Hey1-KO) nor Heyl single-knockout (HeyL-KO) mice show abnormalities in regenerative ability, MyoD and myogenin expression, or MuSC number; however, double-KO mice exhibit severe regenerative defects due to a reduction in MuSC number resulting from increased MyoD and myogenin expression in the MuSCs (Fukada et al, 2011; Noguchi et al, 2019). When MuSCs respond to muscle injury, Hey1 and Heyl expression levels are drastically decreased; therefore, activation/proliferation of MuSCs in injured muscle do not require Hey1 and Heyl expression.…”

Section: Introductionmentioning

confidence: 99%

Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle

Fukuda

Kaneshige

Kaji

et al. 2019

eLife

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In overloaded and regenerating muscle, the generation of new myonuclei depends on muscle satellite cells (MuSCs). Because MuSC behaviors in these two environments have not been considered separately, MuSC behaviors in overloaded muscle remain unexamined. Here, we show that most MuSCs in overloaded muscle, unlike MuSCs in regenerating muscle, proliferate in the absence of MyoD expression. Mechanistically, MuSCs in overloaded muscle sustain the expression of Heyl, a Notch effector gene, to suppress MyoD expression, which allows effective MuSC proliferation on myofibers and beneath the basal lamina. Although Heyl-knockout mice show no impairment in an injury model, in a hypertrophy model, their muscles harbor fewer new MuSC-derived myonuclei due to increased MyoD expression and diminished proliferation, which ultimately causes blunted hypertrophy. Our results show that sustained HeyL expression is critical for MuSC proliferation specifically in overloaded muscle, and thus indicate that the MuSC-proliferation mechanism differs in overloaded and regenerating muscle.

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Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires Hes1 to bind diverse DNA sites

Cited by 38 publications

References 52 publications

LncRNAs are regulated by chromatin states and affect the skeletal muscle cell differentiation

LncRNAs are regulated by chromatin states and affect the skeletal muscle cell differentiation

Androgen receptor in satellite cells is not essential for muscle regenerations

Sustained expression of HeyL is critical for the proliferation of muscle stem cells in overloaded muscle

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