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Epigenomics. 2016 Dec;8(12):1689-1708. Epub 2016 Nov 18.

Yin-yang actions of histone methylation regulatory complexes in the brain.

Author information

Neuroscience Graduate Program, The University of Michigan Medical School, Ann Arbor, MI 48109, USA.
The University of Michigan College of Literature, Science, & The Arts, Ann Arbor, MI 48109, USA.
Department of Human Genetics, The University of Michigan, Ann Arbor, MI 48109, USA.


Dysregulation of histone methylation has emerged as a major driver of neurodevelopmental disorders including intellectual disabilities and autism spectrum disorders. Histone methyl writer and eraser enzymes generally act within multisubunit complexes rather than in isolation. However, it remains largely elusive how such complexes cooperate to achieve the precise spatiotemporal gene expression in the developing brain. Histone H3K4 methylation (H3K4me) is a chromatin signature associated with active gene-regulatory elements. We review a body of literature that supports a model in which the RAI1-containing H3K4me writer complex counterbalances the LSD1-containing H3K4me eraser complex to ensure normal brain development. This model predicts H3K4me as the nexus of previously unrelated neurodevelopmental disorders.


LSD1; PHF21A; RAI1; activity-dependent gene expression; autism spectrum disorders; chromatin regulatory complex; circadian gene expression; histone methylation; intellectual disability; neurodevelopmental disorders

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Conflict of interest statement

Financial & competing interests disclosure PM Garay is supported collectively by an NSF Graduate Research Fellowship Program (DGE #1256260), the University of Michigan Rackham Spring Summer Research Grant Program and the Farrehi Family Foundation. MA Wallner is supported by the University of Michigan Undergraduate Research Opportunity Program (UROP). This work is also supported by the grants to S Iwase from NIH (NS089896) and the University of Michigan Medical School. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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