Scaffolding of the H4K5ac chromatin remodeling complex by lncRNA MAHAC mediates epithelial-mesenchymal transition
Anchoring of a chromatin remodeler complex by long non-coding RNAs (lncRNAs) is a frequently utilized mechanism for lncRNAs to regulate gene expression. Hypoxia is a microenvironemntal condition that plays a crucial role in promoting tumor progression. We previously identified a hypoxia-inducible lncRNA, RP11-390F4.3, that regulates epithelial–mesenchymal transition (EMT) without a delineated mechanism. Here we show that the lncRNA RP11-390F4.3 (renamed MAHAC: MAintenance of Histone ACetylation) specifically induces histone H4 lysine 5 acetylation (H4K5ac) mark and promotes the enrichment of H4K5ac mark on the promoters of EMT transcription factors. MAHAC scaffolds the ILF3/NF90–ILF2–CBP complex, which is co-localized with the members of the complex inside nucleus under hypoxia. The minimal MAHAC region (nt 686–741) required for scaffolding the complex was mapped and it induces allosteric activation of H4K5ac in in vitro histone acetyltransferase assay. This minimal MAHAC region is essential for hypoxia-induced EMT, migration, invasion, and H4K5ac activation. These findings demonstrate that hypoxia-induced MAHAC represents an unexplored allosteric regulator of H4K5ac that activates EMT and induces tumor progression. Overall design: ChIP was conducted following previously established methods (Hsu K.W et al., 2022), using the antibodies H3K4Ac. Each ChIP was carried out with 1 × 10^7 cells and 2 µg of antibody.