Mutually suppressive roles of KMT2A and KDM5C in behaviour, neuronal structure, and histone H3K4 methylation

Commun Biol. 2020 Jun 1;3(1):278. doi: 10.1038/s42003-020-1001-6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Aggression*
  • Animals
  • Craniofacial Abnormalities / genetics*
  • Dendritic Spines / metabolism*
  • Disease Models, Animal
  • Growth Disorders / genetics*
  • Histone Demethylases / deficiency
  • Histone Demethylases / genetics*
  • Histone-Lysine N-Methyltransferase / deficiency
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histones / metabolism*
  • Hypertrichosis / genetics*
  • Intellectual Disability / genetics*
  • Male
  • Mental Retardation, X-Linked / genetics*
  • Methylation
  • Mice
  • Myeloid-Lymphoid Leukemia Protein / deficiency
  • Myeloid-Lymphoid Leukemia Protein / genetics*


  • Histones
  • histone H3 trimethyl Lys4
  • Myeloid-Lymphoid Leukemia Protein
  • Histone Demethylases
  • Kdm5c protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse

Supplementary concepts

  • Mental Retardation, X-Linked, Syndromic, Jarid1c-Related
  • Wiedemann Grosse Dibbern syndrome