JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation

Summary

In our study we demonstrated that TGFb drives multi-enhancer contacts and ultimately gene activation during neuronal commitment. That required the intrinsically disordered region (IDR) of the histone demethylase JMJD3 likely through its role in promoting phase-separated biomolecular condensates.

Abstract

Enhancers are key regulatory elements that govern gene expression programs in response to developmental signals. However, how multiple enhancers arrange in the 3D-space to control the activation of a specific promoter remains unclear. To address this question, we exploited our previously characterized TGFβ-response model, the neural stem cells, focusing on a ~374 kb locus where enhancers abound. Our 4C-seq experiments reveal that the TGFβ pathway drives the assembly of an enhancer cluster and precise gene activation. We discovered that the TGFβ pathway coactivator JMJD3 is essential to maintain these structures. Using live-cell imaging techniques, we demonstrated that an intrinsically disordered region contained in JMJD3 is involved in the formation of phase-separated biomolecular condensates, which are found in the enhancer cluster. Overall, with this work we uncover novel functions for the coactivator JMJD3, and we shed light on the relationships between the 3D-conformation of the chromatin and the TGFβ-driven response during mammalian neurogenesis.

Reference:

Vicioso-Mantis M ^*, Fueyo R^*, Navarro C, Cruz-Molina S, van Ijcken W FJ, Rebollo E, Rada-Iglesias A, and Martínez-Balbás MA (2022) JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation. Nature Communications. 13(1):3263. https://www.nature.com/articles/s41467-022-30614-y