Single substitution in H3.3G34 alters DNMT3A recruitment to cause progressive neurodegeneration [RNA-seq]

ABSTRACT: De novo germline histone H3.3 amino acid substitutions, including H3.3G34R/V, cause severe neurodevelopmental syndromes. To understand how these mutations impact brain development, we generated heterozygous H3.3G34R/V/W direct knock-in mutant mice and identified strikingly distinct developmental defects for each amino acid substitution. H3.3G34R-mutant mice uniquely exhibited progressive microcephaly and neurodegeneration, associated with abnormal accumulation of damage-associated microglia and astrocytes, and concurrent neuronal depletion in postnatal brains. On the mutant H3.3 tail, G34R severely decreased H3K36me2, impairing recruitment of DNA methyltransferase DNMT3A and promoting its redistribution on chromatin. This results in loss of CH methylation at complement and other innate immune genes promoting their sustained expression, and, aberrant CG methylation at neuronal gene promoters and undue silencing. Persistent complement expression in G34R neurons led to excessive synaptic pruning, neuroinflammation, and neuronal damage accounting for progressive neurodegeneration. Our study reveals H3.3G34-substitutions have differential impact on chromatin, which underlie the diverse phenotypes observed. Notably, we uncover unappreciated roles for H3K36me2 and DNMT3A-dependent CH-methylation in modulating pruning and neuroinflammation in post-natal brains.

ORGANISM(S): Mus musculus

PROVIDER: GSE199882 | GEO | 2023/03/16

REPOSITORIES: GEO