| First Author | Marruecos L | Year | 2021 |
| Journal | EMBO Rep | Volume | 22 |
| Issue | 8 | Pages | e52649 |
| PubMed ID | 34224210 | Mgi Jnum | J:358590 |
| Mgi Id | MGI:7782676 | Doi | 10.15252/embr.202152649 |
| Citation | Marruecos L, et al. (2021) Dynamic chromatin association of IkappaBalpha is regulated by acetylation and cleavage of histone H4. EMBO Rep 22(8):e52649 |
| abstractText | IkappaBs exert principal functions as cytoplasmic inhibitors of NF-kB transcription factors. Additional roles for IkappaB homologues have been described, including chromatin association and transcriptional regulation. Phosphorylated and SUMOylated IkappaBalpha (pS-IkappaBalpha) 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 IkappaBalpha favors its binding to nucleosomes and demonstrate that p-IkappaBalpha 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-IkappaBalpha binding. Inhibition of trypsin and chymotrypsin activity in HT29 cells increases p-IkappaBalpha chromatin binding but, paradoxically, impaired goblet cell differentiation, comparable to IkappaBalpha deletion. Taken together, our results indicate that dynamic binding of IkappaBalpha to chromatin is a requirement for intestinal cell differentiation and provide a molecular basis for the understanding of the restricted nuclear distribution of p-IkappaBalpha in specific stem cell compartments. |
