High mobility group N1
protein (
HMGN1), a nucleosomal-
binding protein that affects the structure and function of
chromatin, is encoded by a gene located on chromosome 21 and is overexpressed in
Down syndrome, one of the most prevalent genomic disorders. Misexpression of
HMGN1 affects the cellular transcription profile; however, the
biological function of this
protein is still not fully understood. We report that
HMGN1 modulates the expression of
methyl CpG-binding protein 2 (MeCP2),
a DNA-
binding protein known to affect neurological functions including
autism spectrum disorders, and whose alterations in
HMGN1 levels affect the behavior of mice. Quantitative PCR and Western analyses of cell lines and brain tissues from mice that either overexpress or lack
HMGN1 indicate that
HMGN1 is a negative regulator of MeCP2 expression. Alterations in
HMGN1 levels lead to changes in
chromatin structure and histone modifications in the MeCP2 promoter. Behavior analyses by open field test, elevated plus maze, Reciprocal Social Interaction, and automated sociability test link changes in
HMGN1 levels to abnormalities in activity and anxiety and to social deficits in mice. Targeted analysis of the
Autism Genetic Resource Exchange genotype collection reveals a non-random distribution of genotypes within 500 kbp of
HMGN1 in a region affecting its expression in families predisposed to
autism spectrum disorders. Our results reveal that
HMGN1 affects the behavior of mice and suggest that epigenetic changes resulting from altered
HMGN1 levels could play a role in the etiology of
neurodevelopmental disorders.