Single-cell DNA methylation and 3D genome architecture in the human brain
Wei Tian, Jingtian Zhou, Anna Bartlett, Qiurui Zeng, Hanqing Liu, Rosa Castanon, Mia Kenworthy, Jordan Altshul, Cynthia Valadon, Andrew Aldridge, Joseph R. Nery, Huaming Chen, Jiaying Xu, Nicholas D. Johnson, Jacinta Lucero, Julia Osteen, Nora Emerson, Jon Rink, Jasper Lee, Yang Eric Li, Kimberly Siletti, Michelle Liem, Naomi Claffey, Carolyn O’Connor, Anna Marie Yanny, Julie Nyhus, Nick Dee, Tamara Casper, Nadiya V. Shapovalova, Daniel Hirschstein, Song‐Lin Ding, Rebecca D. Hodge, Boaz P. Levi, C. Dirk Keene, Sten Linnarsson, Ed S. Lein, Bing Ren, M. Margarita Behrens, Joseph R. Ecker
Abstract
Delineating the gene-regulatory programs underlying complex cell types is fundamental for understanding brain function in health and disease. Here, we comprehensively examined human brain cell epigenomes by probing DNA methylation and chromatin conformation at single-cell resolution in 517 thousand cells (399 thousand neurons and 118 thousand non-neurons) from 46 regions of three adult male brains. We identified 188 cell types and characterized their molecular signatures. Integrative analyses revealed concordant changes in DNA methylation, chromatin accessibility, chromatin organization, and gene expression across cell types, cortical areas, and basal ganglia structures. We further developed single-cell methylation barcodes that reliably predict brain cell types using the methylation status of select genomic sites. This multimodal epigenomic brain cell atlas provides new insights into the complexity of cell-type-specific gene regulation in adult human brains.