Cited by 59Genetic Associations and EpidemiologyGenomics and Chromatin DynamicsGenetic Mapping and Diversity in Plants and Animals

Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

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Guo, Michael H., Nandakumar, Satish K., Ulirsch, Jacob C., Zekavat, Seyedeh M., Buenrostro, Jason D., Natarajan, Pradeep, Salem, Rany M., Chiarle, Roberto +14 more·2017·Proceedings of the National Academy of Sciences

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Abstract

Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using high-coverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil count-associated locus near the master hematopoietic transcription factor CEBPA The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.

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  • Interrogation of specific loci identified through studies of population-based variation has uncovered key regulatory mechanisms, such as the role of specific GFI1B isoforms in megakaryopoiesis or the identification of a distinct CEBPA enhancer involved in the production of basophils.

    “In other cases, the interrogation of specific loci identified through studies of population-based variation has uncovered key regulatory mechanisms, such as the role of specific GFI1B isoforms in megakaryopoiesis or the identification of a distinct CEBPA enhancer involved in the production of basophils (Guo et al., 2017; Polfus et al., 2016).”

    From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Guo et al., 2017

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Authors
Guo, M. H., Nandakumar, S. K., Ulirsch, J. C., Zekavat, S. M., Buenrostro, J. D., Natarajan, P., Salem, R. M., Chiarle, R., Mitt, M., Kals, M., Pärn, K., Fischer, K., Milani, L., Mägi, R., Palta, P., Gabriel, S. B., Metspalu, A., Lander, E. S., Kathiresan, S., Hirschhorn, J. N., Esko, T., & Sankaran, V. G.
Affiliations
  • Broad Institute (US)
  • Boston Children's Hospital (US)
  • University of Tartu (EE)
  • University of Helsinki (FI)
Venue
Proceedings of the National Academy of Sciences
Published
2016-12-28
Volume
114
Issue
3
Pages
E327-E336
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W2952573679
Cited by
54
References
105
Citations by year
2026: 1 · 2025: 1 · 2024: 15 · 2023: 6 · 2022: 1 · 2021: 2 · 2020: 5 · 2019: 5 · 2018: 5 · 2017: 13
FWCI
6.18
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, other-oa)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
  • eScholarship (California Digital Library) (submittedVersion)
  • Työväentutkimus Vuosikirja (submittedVersion, other-oa)
Funders
  • HHS | National Institutes of Health (R01 DK103794, R33 HL120791, R01 DK075787)
  • Nordic Information for Action eScience Center by NordForsk (62721)
  • Estonian Research Council (PerMed 1, IUT20-60)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Keywords
hematopoiesis, blood cell traits, basophil count, CEBPA, GATA2, enhancer regulation, myeloid progenitor cells, hematopoietic stem and progenitor cells, lineage specification, fine mapping, epigenomics, Estonian Biobank
MeSH terms
Whole Genome Sequencing, Base Sequence, Basophils, Cell Differentiation, Chromosome Mapping, Enhancer Elements, Genetic, Estonia, Female, Hematopoiesis, Humans, Leukocyte Count, Male, Gene Expression Regulation, Developmental, Cell Lineage, Polymorphism, Single Nucleotide, CCAAT-Enhancer-Binding Proteins, Databases, Nucleic Acid, Epigenesis, Genetic, GATA2 Transcription Factor, Genome-Wide Association Study

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