Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes.
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| Title: | Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes. |
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| Authors: | 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. |
| Source: | Science. 4/4/2025, Vol. 388 Issue 6742, p52-59. 8p. |
| Subjects: | Transcription factors, Genetic variation, Human genome, CRISPRs, Gene expression |
| Abstract: | 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 ~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. Editor's summary: Most genetic variants associated with phenotypes or diseases are located in noncoding regions of the genome that play a crucial role in regulating gene expression. However, the mechanisms through which these variants exert their effects remain largely unclear in most cases. Martin-Rufino et al. have developed "Perturb-multiome," a technology that uses CRISPR to disrupt key regulatory proteins while simultaneously analyzing changes in DNA accessibility and gene activity in individual blood-forming cells. The authors identified critical regions of the human genome that regulate gene expression in response to perturbations, which are essential for shaping blood cell development despite comprising only a small fraction of the genome. This approach facilitates linking genetic variants to their functions across the genome, thereby advancing our understanding of gene regulation in both health and disease. —Di Jiang [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | 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 ~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. Editor's summary: Most genetic variants associated with phenotypes or diseases are located in noncoding regions of the genome that play a crucial role in regulating gene expression. However, the mechanisms through which these variants exert their effects remain largely unclear in most cases. Martin-Rufino et al. have developed "Perturb-multiome," a technology that uses CRISPR to disrupt key regulatory proteins while simultaneously analyzing changes in DNA accessibility and gene activity in individual blood-forming cells. The authors identified critical regions of the human genome that regulate gene expression in response to perturbations, which are essential for shaping blood cell development despite comprising only a small fraction of the genome. This approach facilitates linking genetic variants to their functions across the genome, thereby advancing our understanding of gene regulation in both health and disease. —Di Jiang [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.ads7951 |
