Nuclear IκBα binds to histones H2A and H4 and facilitates Polycomb-dependent HOX gene silencing.
Major finding: Nuclear IκBα binds to histones H2A and H4 and facilitates Polycomb-dependent HOX gene silencing.
Clinical relevance: Nuclear IκBα accumulation decreases with squamous cell carcinoma progression.
Impact: IκBα has a noncanonical nuclear function that is critical to skin homeostasis and development.
The only known activity of IκB proteins is the cytoplasmic sequestration and inhibition of NF-κB. IκB proteins have been found in the nucleus, but their functional significance is unclear. Mulero and colleagues evaluated IκBα localization in human tissues and observed nuclear IκBα staining in the skin, particularly in keratinocytes. Both cytoplasmic and nuclear IκBα could be detected, but phosphorylation and SUMOylation of IκBα were specifically required for its nuclear accumulation. The phosphorylated, SUMOylated nuclear form of IκBα specifically interacted with histones H2A and H4, but not NF-κB, indicating that IκBα can directly bind chromatin in an NF-κB–independent manner. Chromatin immunoprecipitation sequencing in primary human keratinocytes revealed that IκBα binds near promoter and enhancer regions of genes associated with embryonic development and differentiation, including homeobox (HOX) genes. IκBα-occupied loci were also enriched for high levels of the repressive histone H3 lysine 27 trimethylation mark, and overlapped with Polycomb repressive complex (PRC) binding sites. Consistent with these findings pointing to a noncanonical role of IκBα in Polycomb-dependent gene silencing, nuclear IκBα physically interacted with the PRC2 subunit SUZ12, the simultaneous binding of both proteins to IκBα targets was associated with decreased gene expression, and mutation of the Drosophila IκB homolog enhanced the Hox-related extra sex combs phenotype of Polycomb mutant flies independently of the Drosophila NF-κB homolog. Given that deregulated HOX expression occurs in squamous cell carcinomas, which develop from keratinocytes, the authors assessed IκBα localization in transformed keratinocytes and found that nuclear IκBα accumulation was lost in association with decreased PRC2 binding and massive upregulation of IκBα target genes. Moreover, depletion of nuclear IκBα correlated with squamous cell carcinoma progression. These findings point to a role of nuclear IκBα in developmental gene regulation and suggest that loss of nuclear IκBα may be oncogenic.
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