Mutually Suppressive Roles of KMT2A and KDM5C in Behaviour, Neuronal Structure, and Histone H3K4 Methylation

Overview

Journal Commun Biol

Specialty Biology

Date 2020 Jun 3

PMID 32483278

Citations 29

Authors

Christina N Vallianatos

Brynne Raines

Robert S Porter

Katherine M Bonefas

Michael C Wu

Patricia M Garay

Katie M Collette

Young Ah Seo

Yali Dou

Catherine E Keegan

Natalie C Tronson

Shigeki Iwase

Affiliations

Soon will be listed here.

Abstract

Histone H3 lysine 4 methylation (H3K4me) is extensively regulated by numerous writer and eraser enzymes in mammals. Nine H3K4me enzymes are associated with neurodevelopmental disorders to date, indicating their important roles in the brain. However, interplay among H3K4me enzymes during brain development remains largely unknown. Here, we show functional interactions of a writer-eraser duo, KMT2A and KDM5C, which are responsible for Wiedemann-Steiner Syndrome (WDSTS), and mental retardation X-linked syndromic Claes-Jensen type (MRXSCJ), respectively. Despite opposite enzymatic activities, the two mouse models deficient for either Kmt2a or Kdm5c shared reduced dendritic spines and increased aggression. Double mutation of Kmt2a and Kdm5c clearly reversed dendritic morphology, key behavioral traits including aggression, and partially corrected altered transcriptomes and H3K4me landscapes. Thus, our study uncovers common yet mutually suppressive aspects of the WDSTS and MRXSCJ models and provides a proof of principle for balancing a single writer-eraser pair to ameliorate their associated disorders.

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