title: Differential regulation of the histone chaperone HIRA during muscle cell differentiation by a phosphorylation switch.
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.
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
authors: Jae-Hyun
authors: JH
authors: Yang
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
authors: Tae-Yang
authors: TY
authors: Song
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
authors: Chanhee
authors: C
authors: Jo
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
authors: Jinyoung
authors: J
authors: Park
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
authors: Han-Young
authors: HY
authors: Lee
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
authors: Ilang
authors: I
authors: Song
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
authors: Suji
authors: S
authors: Hong
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
authors: Kwan Young
authors: KY
authors: Jung
authors: Department of Biological Sciences Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors: Jaehoon
authors: J
authors: Kim
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
authors: Jeung-Whan
authors: JW
authors: Han
authors: Department of Molecular Medicine & Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, Seoul, Republic of Korea.
authors: Hong-Duk
authors: HD
authors: Youn
authors: School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.
authors: Eun-Jung
authors: EJ
authors: Cho
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D056488:Histone Chaperones / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D024510:Muscle Development; D032446:Myoblasts / Q000166:cytology* / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D018797:Cell Cycle Proteins; C086057:HIRA protein, human; D056488:Histone Chaperones; D006657:Histones; D014157:Transcription Factors; D051057:Proto-Oncogene Proteins c-akt