Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires HeS1 to bind diverse DNA sites

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

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5 Citations (Scopus)

Abstract

The undifferentiated state of muscle stem (satellite) cells (MuSCs) is maintained by the canonical Notch pathway. Although three bHLH transcriptional factors, Hey1, HeyL and Hes1, are considered to be potential effectors of the Notch pathway exerting anti-myogenic effects, neither HeyL nor Hes1 inhibits myogenic differentiation of myogenic cell lines. Furthermore, whether these factors work redundantly or cooperatively is unknown. Here, we showed cell-autonomous functions of Hey1 and HeyL in MuSCs using conditional and genetic null mice. Analysis of cultured MuSCs revealed anti-myogenic activity of both HeyL and Hes1. We found that HeyL forms heterodimeric complexes with Hes1 in living cells. Moreover, our ChIP-seq experiments demonstrated that, compared with HeyL alone, the HeyL-Hes1 heterodimer binds with high affinity to specific sites in the chromatin, including the binding sites of Hey1. Finally, analyses of myogenin promoter activity showed that HeyL and Hes1 act synergistically to suppress myogenic differentiation. Collectively, these results suggest that HeyL and Hey1 function redundantly in MuSCs, and that HeyL requires Hes1 for effective DNA binding and biological activity.

Original languageEnglish
Article numberdev163618
JournalDevelopment (Cambridge)
Volume146
Issue number4
DOIs
Publication statusPublished - Feb 2019

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology

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    Noguchi, Y. T., Nakamura, M., Hino, N., Nogami, J., Tsuji, S., Sato, T., Zhang, L., Tsujikawa, K., Tanaka, T., Izawa, K., Okada, Y., Doi, T., Kokubo, H., Harada, A., Uezumi, A., Gessler, M., Ohkawa, Y., & Fukada, S. I. (2019). Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires HeS1 to bind diverse DNA sites. Development (Cambridge), 146(4), [dev163618]. https://doi.org/10.1242/dev.163618