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Dynamic chromatin association of I?B? is regulated by acetylation and cleavage of histone H4

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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Dynamic association of IκBα to chromatin during intestinal differentiation is regulated by Acetylation and N-terminal cleavage of histone H4

Project description:IκBs exert a principal function as cytoplasmic inhibitors of the NF-kB transcription factors. Additional functions for specific IκB homologues have also been described including their association to chromatin to directly regulate gene transcription. Phosphorylated and SUMOylated IκBα (pS-IκBα) specifically binds histones H2A and H4 in the stem and progenitor compartment of skin and intestine, but the mechanisms that control the recruitment of nuclear pS-IκBα to the chromatin are largely unstudied. We here show thatserine 32-36 phosphorylation of IκBα favors its binding with nucleosomes and demonstrated that p-IκBαassociation to H4 is favored by acetylation at specific H4 lysine (K) residues. Acetylated N-terminal tail of H4 is lost during intestinal cell differentiation due to histone cleavage at amino acids 17-19 by the action of trypsin or chymotrypsin, which interferes p-IκBα association to chromatin. Paradoxically, pharmacologic or genetic inhibition of trypsin and chymotrypsin activity in HT29 cells increased p-IκBα chromatin binding, associated to impaired goblet cell differentiation, which was comparable to IκBα deletion. Together our results indicate that dynamic binding of IκBα to chromatin is a requirement for intestinal cell differentiation and provide a molecular base for the restricted nuclear distribution of p-IκBα at specific stem cell compartments.

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Dynamic association of IκBα to chromatin during intestinal differentiation is regulated by Acetylation and N-terminal cleavage of histone H4

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