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

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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.
Publisher
NATURE PUBLISHING GROUP
Issue Date
2016-08
Language
English
Article Type
Article
Keywords

SKELETAL-MUSCLE; VARIANT H3.3; CHROMATIN; TRANSCRIPTION; REPLICATION; DEPOSITION; DAXX; COMPLEX; HETEROCHROMATIN; ACTIVATION

Citation

EXPERIMENTAL AND MOLECULAR MEDICINE, v.48

ISSN
1226-3613
DOI
10.1038/emm.2016.68
URI
http://hdl.handle.net/10203/219674
Appears in Collection
BS-Journal Papers(저널논문)
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