Integrated Single-Cell Analysis Maps the Continuous Regulatory Landscape of Human Hematopoietic Differentiation
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Human hematopoiesis involves cellular differentiation of multipotent cells into progressively more lineage-restricted states. While the chromatin accessibility landscape of this process has been explored in defined populations, single-cell regulatory variation has been hidden by ensemble averaging. We collected single-cell chromatin accessibility profiles across 10 populations of immunophenotypically defined human hematopoietic cell types and constructed a chromatin accessibility landscape of human hematopoiesis to characterize differentiation trajectories. We find variation consistent with lineage bias toward different developmental branches in multipotent cell types. We observe heterogeneity within common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) and develop a strategy to partition GMPs along their differentiation trajectory. Furthermore, we integrated single-cell RNA sequencing (scRNA-seq) data to associate transcription factors to chromatin accessibility changes and regulatory elements to target genes through correlations of expression and regulatory element accessibility. Overall, this work provides a framework for integrative exploration of complex regulatory dynamics in a primary human tissue at single-cell resolution.
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ATAC-seq can be performed in single cells, revealing cell-to-cell variability and rare epigenomic phenotypes.
“Importantly, ATAC-seq can be performed in single cells (scATAC-seq), uncovering cell-to-cell variability and rare epigenomic phenotypes (Cusanovich et al., 2018; Satpathy et al., 2018; Buenrostro et al., 2018).”
From Coupled Single-Cell CRISPR Screening and Epigenomic Profiling Reveals Causal Gene Regulatory Networks (2019) · cites this paper as Buenrostro et al., 2018
Single-cell measurements of transcriptional states, chromatin accessibility, and DNA methylation have provided a better understanding of heterogeneity in regulatory mechanisms during hematopoiesis.
“Single-cell measurements of transcriptional states, chromatin accessibility, and DNA methylation, have also provided a better understanding of the heterogeneity that exists in such regulatory mechanisms during hematopoiesis (Buenrostro et al., 2018; Cao et al., 2018; Ludwig et al., 2019b; Ulirsch et al., 2019).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Buenrostro et al., 2018
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MLL-AF9 initiates transformation from fast-proliferating myeloid progenitors
Chen, X., Burkhardt, D. B., Hartman, A. A., Hu, X., Eastman, A. E., Sun, C., Wang, X., Zhong, M., Krishnaswamy, S., & Guo, S. (2019) · Nature Communications · doi:10.1038/s41467-019-13666-5 · Cited by 58 · see citing works
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- Authors
- Buenrostro, J. D., Corces, M. R., Lareau, C. A., Wu, B., Schep, A. N., Aryee, M. J., Majeti, R., Chang, H. Y., & Greenleaf, W. J.
- Affiliations
- Broad Institute (US)
- Stanford University (US)
- Stanford Medicine (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Corresponding author
- Buenrostro, Jason D.
- Greenleaf, William J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 173
- Issue
- 6
- Pages
- 1535-1548.e16
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5989727
- OpenAlex
- W2801527818
- Cited by
- 670
- References
- 54
- Citations by year
- 2026: 50 · 2025: 63 · 2024: 74 · 2023: 87 · 2022: 96 · 2021: 108 · 2020: 94 · 2019: 68 · 2018: 28 · 2017: 1
- FWCI
- 27.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (P50HG007735, UM1HG009442, U19AI057266)
- Stinehart-Reed Foundation
- Rita Allen Foundation
- Baxter Foundation Faculty Scholar Grant
- Human Frontiers Science Program (RGY006S)
- Chan Zuckerberg Initiative (2017-174468, 2018-182817)
- Harvard Society of Fellows
- Broad Institute Fellowship
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Keywords
- hematopoiesis, hematopoietic differentiation, chromatin accessibility, common myeloid progenitors, CFU-GM, lineage bias, differentiation trajectories, transcription factors, regulatory elements
- MeSH terms
- Animals, Cell Differentiation, Chromatin, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Humans, Regulatory Sequences, Nucleic Acid, Transcription Factors, Sequence Analysis, RNA, Hematopoietic Stem Cell Transplantation, Cell Lineage, Myeloid Progenitor Cells, Principal Component Analysis, Epigenesis, Genetic, Epigenomics, Single-Cell Analysis, Transcriptome
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