Dynamic chromatin association of I?B? is regulated by acetylation and cleavage of histone H4
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ABSTRACT: I?Bs exert principal functions as cytoplasmic inhibitors of NF-kB transcription factors. Additional roles for I?B homologues have been described, including chromatin association and transcriptional regulation. Phosphorylated and SUMOylated I?B? (pS-I?B?) binds to histones H2A and H4 in the stem cell and progenitor cell compartment of skin and intestine, but the mechanisms controlling its recruitment to chromatin are largely unknown. Here, we show that serine 32-36 phosphorylation of I?B? favors its binding to nucleosomes and demonstrate that p-I?B? association with H4 depends on the acetylation of specific H4 lysine residues. The N-terminal tail of H4 is removed during intestinal cell differentiation by proteolytic cleavage by trypsin or chymotrypsin at residues 17-19, which reduces p-I?B? binding. Inhibition of trypsin and chymotrypsin activity in HT29 cells increases p-I?B? chromatin binding but, paradoxically, impaires goblet cell differentiation, comparable to I?B? deletion. Taken together, our results indicate that dynamic binding of I?B? to chromatin is a requirement for intestinal cell differentiation and provide a molecular basis for the understanding of the restricted nuclear distribution of p-I?B? in specific stem cell compartments.
SUBMITTER: Laura Marruecos
PROVIDER: S-SCDT-EMBOR-2021-52649V1 | biostudies-other |
REPOSITORIES: biostudies-other
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