Abstract
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.
Highlights
The inhibitor of growth (ING) proteins comprising ING1 to ING5 represents an evolutionary conserved family of chromatin regulators that control gene expression [1,2,3,4]
We addressed this important question by employing myogenesis as a paradigm for cell differentiation
These results suggest that the leucine zipper motif, which is critical for ING2 function in myogenesis, endows ING2 with the ability to interact with the Sin3A-HDAC1 complex
Summary
The inhibitor of growth (ING) proteins comprising ING1 to ING5 represents an evolutionary conserved family of chromatin regulators that control gene expression [1,2,3,4]. The expression of ING family members is frequently dysregulated in diverse types of tumors including skin, lung, colorectal and head and neck tumors, suggesting that the ING proteins may play important roles in cancer initiation and progression [3,5,6]. These observations suggest that the ING proteins might play critical roles in cellular homeostasis. The myogenic regulatory factors MyoD and myogenin are members of the basic helix-loop-helix (bHLH) transcription factor family that play key roles in orchestrating myogenesis [10,11,12,13]. How chromatin remodeling by transcriptional regulators might control the expression of key myogenesis regulatory factors is of considerable interest
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