A Chromatin Accessibility Atlas of the Developing Human Telencephalon

Eirene Markenscoff-Papadimitriou; Sean Whalen; Pawel Przytycki; Reuben Thomas; Fadya Binyameen; Tomasz J Nowakowski; Arnold R Kriegstein; Stephan J Sanders; Matthew W State; Katherine S Pollard; John L Rubenstein

doi:10.1016/j.cell.2020.06.002

A Chromatin Accessibility Atlas of the Developing Human Telencephalon

Cell. 2020 Aug 6;182(3):754-769.e18. doi: 10.1016/j.cell.2020.06.002. Epub 2020 Jun 30.

Affiliations

¹ Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.
² Gladstone Institutes, San Francisco, CA, USA.
³ Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Chan-Zuckerberg Biohub, San Francisco, CA, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.
⁶ Gladstone Institutes, San Francisco, CA, USA; Chan-Zuckerberg Biohub, San Francisco, CA, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA; Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA; Quantitative Biology Institute, University of California, San Francisco, San Francisco, CA, USA. Electronic address: katherine.pollard@gladstone.ucsf.edu.
⁷ Department of Psychiatry, Langley Porter Psychiatric Institute, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. Electronic address: john.rubenstein@ucsf.edu.

Abstract

To discover regulatory elements driving the specificity of gene expression in different cell types and regions of the developing human brain, we generated an atlas of open chromatin from nine dissected regions of the mid-gestation human telencephalon, as well as microdissected upper and deep layers of the prefrontal cortex. We identified a subset of open chromatin regions (OCRs), termed predicted regulatory elements (pREs), that are likely to function as developmental brain enhancers. pREs showed temporal, regional, and laminar differences in chromatin accessibility and were correlated with gene expression differences across regions and gestational ages. We identified two functional de novo variants in a pRE for autism risk gene SLC6A1, and using CRISPRa, demonstrated that this pRE regulates SCL6A1. Additionally, mouse transgenic experiments validated enhancer activity for pREs proximal to FEZF2 and BCL11A. Thus, this atlas serves as a resource for decoding neurodevelopmental gene regulation in health and disease.

Keywords: ATAC-seq; autism; chromatin; enhancers; gene regulation; machine learning; neurodevelopment; neuropsychiatric disorders.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autistic Disorder / genetics
Cell Line
Chromatin / genetics*
Chromatin / metabolism*
Chromatin Immunoprecipitation Sequencing
Enhancer Elements, Genetic*
Euchromatin / genetics
GABA Plasma Membrane Transport Proteins / genetics
Gene Expression Regulation, Developmental / genetics*
Gene Ontology
Genetic Predisposition to Disease
Gestational Age
Humans
Mice
Mice, Transgenic
Nucleotide Motifs
Point Mutation
Prefrontal Cortex / embryology*
Prefrontal Cortex / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Spatio-Temporal Analysis
Telencephalon / embryology*
Telencephalon / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

BCL11A protein, human
Chromatin
Euchromatin
FEZF2 protein, human
GABA Plasma Membrane Transport Proteins
Repressor Proteins
SLC6A1 protein, human
Transcription Factors

A Chromatin Accessibility Atlas of the Developing Human Telencephalon

Authors

Affiliations

Abstract

Publication types

MeSH terms

Substances

Grants and funding