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

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

doi:10.1016/j.celrep.2021.110089

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

Cell Rep. 2021 Dec 7;37(10):110089. doi: 10.1016/j.celrep.2021.110089.

Affiliations

¹ Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA. Electronic address: Eirene.Markenscoff-Papadimitriou@ucsf.edu.
² Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
³ Gladstone Institutes, San Francisco, CA, USA.
⁴ Departments of Neurobiology, Physiology, and Behavior and Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA.
⁵ Department of Radiology.
⁶ Gladstone Institutes, San Francisco, CA, USA; Chan-Zuckerberg Biohub, San Francisco, CA, USA; Institute for Computational Health Sciences, University of California, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA; Quantitative Biology Institute, University of California, San Francisco, CA, USA.
⁷ Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, CA, USA. Electronic address: John.Rubenstein@ucsf.edu.

Abstract

Deleterious genetic variants in POGZ, which encodes the chromatin regulator Pogo Transposable Element with ZNF Domain protein, are strongly associated with autism spectrum disorder (ASD). Although it is a high-confidence ASD risk gene, the neurodevelopmental functions of POGZ remain unclear. Here we reveal the genomic binding of POGZ in the developing forebrain at euchromatic loci and gene regulatory elements (REs). We profile chromatin accessibility and gene expression in Pogz^-/- mice and show that POGZ promotes the active chromatin state and transcription of clustered synaptic genes. We further demonstrate that POGZ forms a nuclear complex and co-occupies loci with ADNP, another high-confidence ASD risk gene, and provide evidence that POGZ regulates other neurodevelopmental disorder risk genes as well. Our results reveal a neurodevelopmental function of an ASD risk gene and identify molecular targets that may elucidate its function in ASD.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Autistic Disorder / enzymology*
Autistic Disorder / genetics
Autistic Disorder / physiopathology
Binding Sites
Brain / enzymology*
Brain / growth & development
Cell Cycle Proteins / genetics
Cell Cycle Proteins / physiology*
Chromatin Assembly and Disassembly*
DNA Transposable Elements
DNA-Binding Proteins / genetics
DNA-Binding Proteins / physiology*
Enhancer Elements, Genetic
Euchromatin / genetics
Euchromatin / metabolism*
Female
Gene Expression Regulation, Developmental
Genetic Predisposition to Disease
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Neurogenesis
Promoter Regions, Genetic
Synapses / enzymology*
Synapses / genetics
Transposases / genetics
Transposases / metabolism*

Substances

ADNP protein, human
Adnp protein, mouse
Cell Cycle Proteins
DNA Transposable Elements
DNA-Binding Proteins
Euchromatin
Homeodomain Proteins
Nerve Tissue Proteins
POGZ protein, human
Pogz protein, mouse
Transposases

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

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding