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Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes

By Eirene Markenscoff, Fadya Binyameen, Sean Whalen, James Price, Kenneth Lim, Rinaldo Catta-Preta, Emily Ling-Lin Pai, Xin Mu, Duan Xu, Katherine Pollard, Alex Nord, Matthew W. State, John L.R. Rubenstein

Posted 08 Apr 2021
bioRxiv DOI: 10.1101/2021.04.07.438852

De novo mutations in POGZ, which encodes the chromatin regulator Pogo Transposable Element with ZNF Domain protein, are strongly associated with autism spectrum disorder (ASD). Here we find that in the developing mouse and human brain POGZ binds predominantly euchromatic loci and these are enriched for human neurodevelopmental disorder genes and transposable elements. We profile chromatin accessibility and gene expression in Pogz-/- mice and find that POGZ promotes chromatin accessibility of candidate regulatory elements (REs) and the expression of clustered synaptic genes. We further demonstrate that POGZ forms a nuclear complex and co-occupies loci with HP1gamma and ADNP, another high-confidence ASD risk gene. In Pogz+/- mice, Adnp expression is reduced. We postulate that reduced POGZ dosage disrupts cortical function through alterations in the POGZ-ADNP balance which modifies neuronal gene expression.

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