- Main
Three-dimensional epigenomic characterization reveals insights into gene regulation and disease in the human brain
- Song, Michael
- Advisor(s): Shen, Yin
Abstract
Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell type-specificity and difficulties in characterizing their regulatory targets, our ability to identify causal genetic variants has remained limited. To address these constraints, we perform integrative analysis of chromatin interactions, open chromatin regions, and transcriptomes for four neural cell types: iPSC-induced excitatory neurons, iPSC-derived hippocampal dentate gyrus (DG)-like neurons, iPSC-induced lower motor neurons, and primary astrocytes. Furthermore, we analyze radial glia (RG), intermediate progenitor cells (IPCs), excitatory neurons (eNs), and interneurons (iNs) isolated from mid-gestational human cortex samples. We utilize the chromatin interactions to link the promoters for genes participating in key neurological processes to distal regulatory elements such as enhancers and silencers that may be dysregulated in disease. In addition, we identify a novel chromatin feature which underlies cell type-specific transcription, which we term super interactive promoters (SIPs). Finally, we validate distal regulatory elements in both RG and eNs using CRISPR techniques as well as CRISPRview, a novel technique we developed for validating cell type-specific cis-regulatory elements in heterogeneous populations of primary cells. This work presents the first characterization of cell type-specific 3D epigenomes in these neurologically relevant cell types, advancing our knowledge of gene regulation during human brain development and complex neuropsychiatric disorders.
Main Content
Enter the password to open this PDF file:
-
-
-
-
-
-
-
-
-
-
-
-
-
-