Methyl-CpG binding domain 2 (Mbd2) is an Epigenetic Regulator of Autism-Risk Genes and Cognition

Elad Lax, Sonia DoCarmo, Yehoshua Enuka, Daniel M. Sapozhnikov, Lindsay A. Welikovitch, Niaz Mahmood, Shafaat A. Rabbani, Liqing Wang, Jonathan P. Britt, Wayne W. Hancock, Yosef Yarden, Moshe Szyf

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Mar 01, 2019

Received Date: 13th February 19

The Methyl-CpG-Binding Domain Protein family has been implicated in neurodevelopmental disorders. The Methyl-CpG-binding domain 2 (Mbd2) binds methylated DNA and was shown to play an important role in cancer and immunity. Some evidence linked this protein to neurodevelopment. However, its exact role in neurodevelopment and brain function is mostly unknown. Here we show that Mbd2-deficiency in mice (Mbd2-/-) results in deficits in cognitive, social and emotional functions. Mbd2 binds regulatory DNA regions of neuronal genes in the hippocampus and loss of Mbd2 alters the expression of hundreds of genes with a robust down-regulation of neuronal gene pathways. Further, a genome-wide DNA methylation analysis found an altered DNA methylation pattern in regulatory DNA regions of neuronal genes in Mbd2-/- mice. Differentially expressed genes significantly overlap with gene-expression changes observed in brain of Autism Spectrum Disorder (ASD) individuals. Notably, down-regulated genes are significantly enriched for human ortholog ASD risk-genes. Observed hippocampal morphological abnormalities were similar to those found in individuals with ASD and ASD rodent models. Mbd2 knockdown partially recapitulates  the behavioral phenotypes observed in Mbd2-/- mice.

These findings suggest Mbd2 is a novel epigenetic regulator of genes that are associated with ASD in humans. Mbd2 loss causes behavioral alterations that resemble those found in ASD patients.

Read in full at bioRxiv.

This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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