Lysyl Oxidase – Like 2 ( LOXL 2 ) Oxidizes

Methylation of histone H3 lysine 4 is linked to active transcription and can be removed by LSD1 or the JmjC domain–containing proteins by amino-oxidation or hydroxylation, respectively. Here we describe that its deamination can be catalyzed by lysyl oxidase–like 2 protein (LOXL2), presenting an unconventional chemical mechanism for H3K4 modification. Infrared spectroscopy and mass spectrometry analyses demonstrated that recombinant LOXL2 specifically deaminates trimethylated H3K4. Moreover, by regulating H3K4me3 deamination, LOXL2 activity is linked with the transcriptional control of the CDH1 gene. These results reveal the existence of further H3 modification as well as a novel mechanism for H3K4me3 demethylation. A cc ep te d A rt ic le This article is protected by copyright. All rights reserved. INTRODUCTION Transcriptional regulation involves interactions between transcription factors and chromatinmodifying complexes [1] that lead to changes in chromatin structure and histone modifications. One of the modifications linked to active transcription is histone methylation at lysine 4 [2]. LSD1 and JmjC domain–containing proteins are the enzymes identified to be responsible for H3K4 demethylation [3-5]. Several observations suggest the existence of additional demethylases that use other chemical mechanisms to demethylate lysine residues within histone H3 [6]. Here, we demonstrate that LOXL2, a Snail1-interacting protein [7], catalyzes an amino oxidase reaction to deaminate trimethylated lysine 4 in histone H3. LOXL2 is member of the lysyl oxidase (LOX) protein family, which are copper-containing enzymes that catalyze the oxidative deamination of the ε-amino groups in lysines [8]. While it is known that LOXL2 is involved in CDH1 repression and EMT induction [7], the specific mechanism of action remains elusive. We now find that LOXL2 is a histone modifier enzyme that removes trimethylated lysine 4 (K4) in histone H3 (H3K4me3) through an amino-oxidase reaction. As a result of LOXL2 oxidation, the trimethylated amino group is released, converting K4 into an allysine (H3K4ox). This study thus reveals the existence of a new type of modified H3.