Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes
成果类型：
Article
署名作者：
Martin-Rufino, Jorge Diego; Caulier, Alexis; Lee, Seayoung; Castano, Nicole; King, Emily; Joubran, Samantha; Jones, Marcus; Goldman, Seth R.; Arora, Uma P.; Wahlster, Lara; Lander, Eric S.; Sankaran, Vijay G.
署名单位：
Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Howard Hughes Medical Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Massachusetts Institute of Technology (MIT); Harvard University; Harvard Medical School; Harvard University
刊物名称：
SCIENCE
ISSN/ISSBN：
0036-11146
DOI：
10.1126/science.ads7951
发表日期：
2025-04-04
页码：
52-59
关键词：
single-cell
hematopoiesis
identification
interrogation
expression
RESOLUTION
variants
reveals
traits
state
摘要：
Most phenotype-associated genetic variants map to noncoding regulatory regions of the human genome, but their mechanisms remain elusive in most cases. We developed a highly efficient strategy, Perturb-multiome, to simultaneously profile chromatin accessibility and gene expression in single cells with CRISPR-mediated perturbation of master transcription factors (TFs). We examined the connection between TFs, accessible regions, and gene expression across the genome throughout hematopoietic differentiation. We discovered that variants within TF-sensitive accessible chromatin regions in erythroid differentiation, although representing <0.3% of the genome, show a similar to 100-fold enrichment for blood cell phenotype heritability, which is substantially higher than that for other accessible chromatin regions. Our approach facilitates large-scale mechanistic understanding of phenotype-associated genetic variants by connecting key cis-regulatory elements and their target genes within gene regulatory networks.