Ancestral function of Inhibitors-of-kappaB regulatesCaenorhabditis elegansdevelopment

Abstract

Mammalian IκB proteins (IκBs) exert their main function as negative regulators of NF-κB, a central signaling pathway controlling immunity and inflammation. An alternative chromatin role for IκBs has been shown to affect stemness and cell differentiation. However, the involvement of NF-κB in this function has not been excluded. NFKI-1 and IKB-1 are IκB homologs in Caenorhabditis elegans, which lacks NF-κB nuclear effectors. We found that nfki-1 and ikb-1 mutants display developmental defects that phenocopy mutations in Polycomb and UTX-1 histone demethylase, suggesting a role for C. elegans IκBs in chromatin regulation. Further supporting this possibility (i) we detected NFKI-1 in the nucleus of cells; (ii) NFKI-1 and IKB-1 bind to histones and Polycomb proteins, (iii) and associate with chromatin in vivo, and (iv) mutations in nfki-1 and ikb-1 alter chromatin marks. Based on these results, we propose that ancestral IκB inhibitors modulate Polycomb activity at specific gene subsets with an impact on development.

Dynamic association of IκBα to chromatin is regulated by acetylation and cleavage of histone H4

“…and 5D) or knocking down trypsin or chymotrypsin with different shRNA (Figure 5E, 5F and S3) both precluded goblet cell differentiation of HT29 cells, comparable to the effects imposed by IκBα deletion. These results suggest that histone cleavage, which favors dissociation of IκBα from the chromatin, is required for intestinal cell differentiation.Together our results support a model in which dynamic binding/dissociation of IκBα to/from chromatin regulates specific gene transcription, which is essential for stem cell maturation and subsequent progression towards tissue-specific mature lineages(Brena et al, 2020;Marruecos et al, 2020;Mulero et al, 2013 and this work). Thus, in the absence of chromatin-bound IκBα or in case of irreversible IκBα chromatin binding (i.e.…”