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Positive Feedback Regulation in Histone Demethylases
Author(s) -
Fujimori Danica
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.224.2
Subject(s) - demethylase , biology , chromatin , epigenetics , dna demethylation , histone methylation , histone , transcription (linguistics) , transcriptional regulation , microbiology and biotechnology , dna methylation , transcription factor , genetics , biochemistry , dna , gene expression , gene , linguistics , philosophy
Histone demethylases are chromatin‐modifying enzymes that antagonize lysine methylation. Despite their crucial roles in regulating transcription in physiology and disease, the mechanisms by which demethylases are regulated on chromatin are largely unknown. This is particularly the case for the jumonji subfamily of demethylases, the most recently discovered family of epigenetic enzymes. The need to mechanistically dissect the function of these enzymes rests on evidence that jumonji demethylases are important regulators of transcription in development and differentiation, and that several of these enzymes act as oncogenes. By investigating the regulation of catalysis in demethylase KDM5A, we have uncovered a novel allosteric mechanism that regulates the activity of this enzyme. Specifically, we demonstrated that binding of the product of demethylation catalysis to one of three PHD reader domains in KDM5A strongly stimulates the catalytic activity of this enzyme. Our findings expand the function of reader domains in jumonji demethylases beyond their canonical function in the recruitment. The unprecedented functional coupling between a PHD domain liganded with the demethylation product and a catalytic domain reveals positive feedback regulation and provides a mechanism by which demethylation could spread on chromatin.