The Histone Variant MacroH2A1.2 Is Necessary for the Activation of Muscle Enhancers and Recruitment of the Transcription Factor Pbx1
Stefania Dell’Orso,
A. Hongjun Wang,
Han-Yu Shih,
Kayoko Saso,
Libera Berghella,
Gustavo Gutierrez-Cruz,
Andreas G. Ladurner,
John J. O’Shea,
Vittorio Sartorelli,
Hossein Zare
Affiliations
Stefania Dell’Orso
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA
A. Hongjun Wang
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA
Han-Yu Shih
Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA
Kayoko Saso
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA
Libera Berghella
Epigenetics and Regenerative Medicine, IRCCS Fondazione Santa Lucia, 00143 Rome, Italy
Gustavo Gutierrez-Cruz
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA
Andreas G. Ladurner
Butenandt Institute, LMU Biomedical Center, Department of Physiological Chemistry, Ludwig-Maximilians-University of Munich, 81377 Munich, Germany
John J. O’Shea
Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD 20892, USA
Vittorio Sartorelli
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA; Corresponding author
Hossein Zare
Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA
Summary: Histone variants complement and integrate histone post-translational modifications in regulating transcription. The histone variant macroH2A1 (mH2A1) is almost three times the size of its canonical H2A counterpart, due to the presence of an ∼25 kDa evolutionarily conserved non-histone macro domain. Strikingly, mH2A1 can mediate both gene repression and activation. However, the molecular determinants conferring these alternative functions remain elusive. Here, we report that mH2A1.2 is required for the activation of the myogenic gene regulatory network and muscle cell differentiation. H3K27 acetylation at prospective enhancers is exquisitely sensitive to mH2A1.2, indicating a role of mH2A1.2 in imparting enhancer activation. Both H3K27 acetylation and recruitment of the transcription factor Pbx1 at prospective enhancers are regulated by mH2A1.2. Overall, our findings indicate a role of mH2A1.2 in marking regulatory regions for activation. : Dell’Orso et al. report that the histone variant macroH2A1.2 is required for activation of muscle-gene expression and cell differentiation. Genome-wide analyses indicate that macroH2A1.2 is enriched at prospective muscle-specific enhancers where it is required for H3K27 acetylation and recruitment of the transcription factor Pbx1.
