Identification of a novel function for the chromatin remodeling protein ING2 in muscle differentiation.
The inhibitor of growth (ING) family of zinc-finger plant homeodomain (PHD)-containing chromatin remodeling protein controls gene expression and has been implicated in the regulation of cell proliferation and death. However, the role of ING proteins in cell differentiation remains largely unexplored. Here, we identify an essential function for ING2 in muscle differentiation. We find that knockdown of ING2 by RNA interference (RNAi) blocks the differentiation of C2C12 cells into myotubes, suggesting that ING2 regulates the myogenic differentiation program. We also characterize a mechanism by which ING2 drives muscle differentiation. In structure-function analyses, we find that the leucine zipper motif of ING2 contributes to ING2-dependent muscle differentiation. By contrast, the PHD domain, which recognizes the histone H3K4me3 epigenetic mark, inhibits the ability of ING2 to induce muscle differentiation. We also find that the Sin3A-HDAC1 chromatin remodeling complex, which interacts with ING2, plays a critical role in ING2-dependent muscle differentiation. These findings define a novel function for ING2 in muscle differentiation and bear significant implications for our understanding of the role of the ING protein family in cell differentiation and tumor suppression.
Southern Alberta Cancer Research Institute, Departments of Biochemistry and Molecular Biology and Oncology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Shawn A
SA
Eapen
Stuart J
SJ
Netherton
Krishna P
KP
Sarker
Lili
L
Deng
Angela
A
Chan
Karl
K
Riabowol
Shirin
S
Bonni
D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation; D042002:Chromatin Assembly and Disassembly; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D016350:Leucine Zippers; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D032342:Muscle Cells / Q000166:cytology / Q000378:metabolism; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
D006657:Histones; D018398:Homeodomain Proteins; C512177:ING2 protein, mouse; D025521:Tumor Suppressor Proteins; D008239:Lysine