- Howard Hughes Medical Institute, Department of Cardiology, Boston Children’s Hospital, Enders Building 1309, 320 Longwood Avenue, Boston, MA 02115, USA
- Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA
- Corresponding author
- •The ubiquitous chanzyme TRPM7 is cleaved in a cell-type-specific fashion
- •Cleaved kinase translocate to the nucleus and binds transcription factors
- •Zinc entry via TRPM7 increases kinase binding to transcription factors
- •The kinase phosphorylates H3S10, H3S28, and H3T3 to alter transcription
TRPM7 is a ubiquitous ion channel and kinase, a unique “chanzyme,” required for proper early embryonic development. It conducts Zn2+, Mg2+, and Ca2+ as well as monovalent cations and contains a functional serine/threonine kinase at its carboxyl terminus. Here, we show that in normal tissues and cell lines, the kinase is proteolytically cleaved from the channel domain in a cell-type-specific manner. These TRPM7 cleaved kinase fragments (M7CKs) translocate to the nucleus and bind multiple components of chromatin-remodeling complexes, including Polycomb group proteins. In the nucleus, the kinase phosphorylates specific serines/threonines of histones. M7CK-dependent phosphorylation of H3Ser10 at promoters of TRPM7-dependent genes correlates with their activity. We also demonstrate that cytosolic free [Zn2+] is TRPM7 dependent and regulates M7CK binding to transcription factors containing zinc-finger domains. These findings suggest that TRPM7-mediated modulation of intracellular Zn2+ concentration couples ion-channel signaling to epigenetic chromatin covalent modifications that affect gene expression patterns.