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Intrinsically disordered regions restrain genomic targeting of RNA and histone demethylases in mammals and plants
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DOI：10.1038/s41588-026-02685-w.png)
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Abstract
En 中文
Intrinsically disordered regions (IDRs) are widely recognized as facilitators of chromatin regulation. However, their potential role as regulatory restraints remains poorly understood. 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. IDR deletion redirects ALKBH5 to chromatin-associated noncoding 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. Building on these insights, we applied IDR deletion to engineer ALKBH5 and its plant homologs. Overexpression of these IDR-deleted ALKBH5 demethylases enhanced Arabidopsis root growth and markedly increased rice yield. Our findings uncover a conserved role for IDRs in restraining chromatin access by RNA and histone demethylases and establish a strategy to reprogram chromatin through endogenous plant proteins for crop improvement. Intrinsically disordered regions impose regulatory restraints on gene-activating demethylases, limiting chromatin engagement and preserving genomic stability. This function is a key determinant of the distinct substrate preferences and regulatory activities of FTO and ALKBH5 in mammals and plants.
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