Intrinsically disordered regions restrain genomic targeting of RNA and histone demethylases in mammals and plants [Histone LCD]

Here, we reveal that the C-terminal IDR of mammalian ALKBH5 anchors its main activity to mRNA, limiting chromatin engagement in mouse embryonic stem cells (mESCs). IDR deletion redirects ALKBH5 to chromatin-associated non-coding RNAs, driving widespread chromatin opening and transcriptional activation.

This mechanism extends to histone demethylases, where IDR deletion also results in broad removal of repressive histone marks, leading to increased chromatin accessibility and activation of transposable elements. Leveraging these insights, we engineered plant ALKBH5 homologs with IDR deletion. Overexpression of these IDR-deleted plant RNA demethylases could promote Arabidopsis root growth and significantly increase rice yield.