Exp Mol Med.  2016 Aug;48(8):e252. 10.1038/emm.2016.68.

Differential regulation of the histone chaperone HIRA during muscle cell differentiation by a phosphorylation switch

Affiliations
  • 1School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea. echo@skku.edu
  • 2Department of Biological Sciences Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
  • 3Department of Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, Seoul, Republic of Korea.

Abstract

Replication-independent incorporation of variant histone H3.3 has a profound impact on chromatin function and numerous cellular processes, including the differentiation of muscle cells. The histone chaperone HIRA and H3.3 have essential roles in MyoD regulation during myoblast differentiation. However, the precise mechanism that determines the onset of H3.3 deposition in response to differentiation signals is unclear. Here we show that HIRA is phosphorylated by Akt kinase, an important signaling modulator in muscle cells. By generating a phosphospecific antibody, we found that a significant amount of HIRA was phosphorylated in myoblasts. The phosphorylation level of HIRA and the occupancy of phosphorylated protein on muscle genes gradually decreased during cellular differentiation. Remarkably, the forced expression of the phosphomimic form of HIRA resulted in reduced H3.3 deposition and suppressed the activation of muscle genes in myotubes. Our data show that HIRA phosphorylation limits the expression of myogenic genes, while the dephosphorylation of HIRA is required for proficient H3.3 deposition and gene activation, demonstrating that the phosphorylation switch is exploited to modulate HIRA/H3.3-mediated muscle gene regulation during myogenesis.


MeSH Terms

Antibodies, Phospho-Specific
Chromatin
Histones*
Muscle Cells*
Muscle Development
Muscle Fibers, Skeletal
Myoblasts
Phosphorylation*
Phosphotransferases
Transcriptional Activation
Antibodies, Phospho-Specific
Chromatin
Histones
Phosphotransferases
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