|
Status |
Public on Apr 25, 2020 |
Title |
A Chromatin Accessibility Atlas of the Developing Human Telencephalon |
Organism |
Homo sapiens |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
Summary |
Gene expression differs between cell types and regions within complex tissues such as the developing brain. To discover regulatory elements underlying this specificity, we generated genome-wide maps of chromatin accessibility in nine anatomically-defined regions of the developing human telencephalon. Additionally, we defined the histone modification landscape of the prefrontal cortex and generated chromatin accessibility maps of its upper and deep layers. We predicted a subset of open chromatin regions (18%) that are most likely to be active enhancers, many of which are dynamic with 26% differing between early and late mid-gestation and 28% present in only one brain region. These predicted regulatory elements (pREs) are enriched proximal to genes with expression differences across developmental stages, regions, and cortical laminae; they harbor distinct sequence motifs that suggest potential upstream regulators. We leveraged this atlas to predict and validate novel regulatory elements of genes that control cortex laminar identity and genes associated with autism spectrum disorder (ASD). These include enhancers proximal to FEZF2 and BCL11A that were validated in mouse, and an enhancer of ASD gene SLC6A1 containing two functional de novo mutations in individuals with ASD whose enhancer function we validated via CRISPRa. These applications demonstrate the utility of this atlas for decoding neurodevelopmental gene regulation in health and disease.
|
|
|
Overall design |
We performed ATAC-seq on nuclei isolated from fresh samples of human fetal hemispheres. Nine separate brain regions were dissected. In prefrontal cortex, for some samples we microdissected upper and deep layers of the cortical plate. We performed ChIP-seq on native chromatin isolated from nuclei from the prefrontal cortex using antibodies for different histone modifications. Submitter declares that the human raw data will be deposited in dbGaP due to patient privacy concerns.
|
|
|
Contributor(s) |
Markenscoff-Papadimitriou E, Whalen S, Pollard K, Rubenstein J |
Citation(s) |
32610082 |
|
Submission date |
Apr 24, 2020 |
Last update date |
Jul 25, 2020 |
Contact name |
John Rubenstein |
Organization name |
University of California, San Francisco
|
Department |
Department of Psychiatry
|
Street address |
401 Parnassus Ave
|
City |
San Francisco |
State/province |
CA |
ZIP/Postal code |
94143 |
Country |
USA |
|
|
Platforms (2) |
GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
GPL27467 |
Illumina Hiseq 2500 (Homo sapiens) |
|
Samples (40)
|
|
Relations |
BioProject |
PRJNA627850 |