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] |
| Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
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| Header | DbId: pbh DbLabel: Psychology and Behavioral Sciences Collection An: 188103712 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Martin-Rufino%2C+Jorge+Diego%22">Martin-Rufino, Jorge Diego</searchLink><br /><searchLink fieldCode="AR" term="%22Caulier%2C+Alexis%22">Caulier, Alexis</searchLink><br /><searchLink fieldCode="AR" term="%22Lee%2C+Seayoung%22">Lee, Seayoung</searchLink><br /><searchLink fieldCode="AR" term="%22Castano%2C+Nicole%22">Castano, Nicole</searchLink><br /><searchLink fieldCode="AR" term="%22King%2C+Emily%22">King, Emily</searchLink><br /><searchLink fieldCode="AR" term="%22Joubran%2C+Samantha%22">Joubran, Samantha</searchLink><br /><searchLink fieldCode="AR" term="%22Jones%2C+Marcus%22">Jones, Marcus</searchLink><br /><searchLink fieldCode="AR" term="%22Goldman%2C+Seth+R%2E%22">Goldman, Seth R.</searchLink><br /><searchLink fieldCode="AR" term="%22Arora%2C+Uma+P%2E%22">Arora, Uma P.</searchLink><br /><searchLink fieldCode="AR" term="%22Wahlster%2C+Lara%22">Wahlster, Lara</searchLink><br /><searchLink fieldCode="AR" term="%22Lander%2C+Eric+S%2E%22">Lander, Eric S.</searchLink><br /><searchLink fieldCode="AR" term="%22Sankaran%2C+Vijay+G%2E%22">Sankaran, Vijay G.</searchLink> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Science%22">Science</searchLink>. 4/4/2025, Vol. 388 Issue 6742, p52-59. 8p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Transcription+factors%22">Transcription factors</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+variation%22">Genetic variation</searchLink><br /><searchLink fieldCode="DE" term="%22Human+genome%22">Human genome</searchLink><br /><searchLink fieldCode="DE" term="%22CRISPRs%22">CRISPRs</searchLink><br /><searchLink fieldCode="DE" term="%22Gene+expression%22">Gene expression</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: 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] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
| PLink | https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=188103712 |
| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1126/science.ads7951 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 8 StartPage: 52 Subjects: – SubjectFull: Transcription factors Type: general – SubjectFull: Genetic variation Type: general – SubjectFull: Human genome Type: general – SubjectFull: CRISPRs Type: general – SubjectFull: Gene expression Type: general Titles: – TitleFull: Transcription factor networks disproportionately enrich for heritability of blood cell phenotypes. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Martin-Rufino, Jorge Diego – PersonEntity: Name: NameFull: Caulier, Alexis – PersonEntity: Name: NameFull: Lee, Seayoung – PersonEntity: Name: NameFull: Castano, Nicole – PersonEntity: Name: NameFull: King, Emily – PersonEntity: Name: NameFull: Joubran, Samantha – PersonEntity: Name: NameFull: Jones, Marcus – PersonEntity: Name: NameFull: Goldman, Seth R. – PersonEntity: Name: NameFull: Arora, Uma P. – PersonEntity: Name: NameFull: Wahlster, Lara – PersonEntity: Name: NameFull: Lander, Eric S. – PersonEntity: Name: NameFull: Sankaran, Vijay G. IsPartOfRelationships: – BibEntity: Dates: – D: 04 M: 04 Text: 4/4/2025 Type: published Y: 2025 Identifiers: – Type: issn-print Value: 00368075 Numbering: – Type: volume Value: 388 – Type: issue Value: 6742 Titles: – TitleFull: Science Type: main |
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