Reducing methylation of histone 3.3 lysine 4 in the medial ganglionic eminence and hypothalamus recapitulates neurodevelopmental disorder phenotypes

TL;DR

This study shows that disrupting histone methylation in specific brain regions leads to symptoms resembling neurodevelopmental disorders, including intellectual disability and growth issues.

Contribution

The study demonstrates that H3K4 methylation disruption in the MGE and hypothalamus recapitulates NDD phenotypes, including sex-biased severity.

Findings

Disrupted H3K4 methylation leads to fewer forebrain interneurons and increased seizure susceptibility.

Mutant mice show altered hypothalamic function, resulting in growth deficits and later obesity.

Single nuclei sequencing reveals transcriptional changes underlying NDD-like behaviors.

Abstract

Methylation of lysine 4 on histone H3 (H3K4) is enriched on active promoters and enhancers where it promotes gene activation. Disruption of H3K4 methylation is associated with numerous neurodevelopmental diseases (NDDs) that display intellectual disability and abnormal body growth. Here, we perturb H3K4 methylation in the medial ganglionic eminence (MGE) and hypothalamus, two brain regions associated with these disease phenotypes. These mutant mice have fewer forebrain interneurons, deficient network rhythmogenesis, and increased spontaneous seizures and seizure susceptibility. Mutant mice are significantly smaller than control littermates, but they eventually became obese due to striking changes in the genetic and cellular hypothalamus environment in these mice. Perturbation of H3K4 methylation in these cells produces deficits in numerous NDD-associated behaviors, with a bias for more severe phenotypes in female mice. Single nuclei sequencing reveals transcriptional changes in the embryonic and adult brain that underlie many of these phenotypes. In sum, our findings highlight the critical role of H3K4 methylation in regulating survival and cell-specific gene regulatory mechanisms in forebrain GABAergic and hypothalamic cells during neurodevelopment to control network excitability and body size homoeostasis.

Dysregulation of H3K4 methylation is associated with neurodevelopmental disorders. Here, the authors perturb H3K4 methylation in the MGE and hypothalamus, resulting in altered gene expression and cell fate as well as changes in behavior that mimic NDD symptoms.

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