Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Densely interconnected transcriptional circuits control cell states in human hematopoiesis

ABSTRACT: Tremendous progress has been made in identifying individual transcription factors that regulate hematopoietic differentiation, but many aspects of the global architecture of hematopoiesis remain unknown. Here, we profiled gene expression in 38 distinct purified populations of human hematopoietic cells and used probabilistic models of gene expression patterns and sequence-based analysis of motifs in gene promoters to decipher the general organization of their regulatory circuitry. We identified modules of highly co-expressed genes, some of which are restricted to a single lineage, but most are expressed at variable levels across multiple lineages. We found densely interconnected cis-regulatory circuits and a large number of transcription factors that are differentially expressed across hematopoietic states, suggesting a more complex regulatory system than previously assumed. We functionally validated a subset of candidate factors using RNA interference and ChIP-Seq. Our dataset, analytic tools, and findings, available on a web-based portal, provide a unique resource to study the regulatory architecture of hematopoiesis. We defined 38 distinct hematopoietic cell states based on cell surface marker expression, representing hematopoietic stem and progenitor cells, terminally differentiated cells, and intermediate states. For each state, we purified samples separately from 4 to 7 independent donors by multiparameter flow cytometry, yielding 211 profiled samples. Cells from all stem and progenitor populations were purified from umbilical cord blood. Terminally differentiated lymphocyte populations were purified from peripheral blood.

ORGANISM(S): Homo sapiens

SUBMITTER: Noa Novershtern

PROVIDER: E-GEOD-24759 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Densely interconnected transcriptional circuits control cell states in human hematopoiesis.

Novershtern Noa N Subramanian Aravind A Lawton Lee N LN Mak Raymond H RH Haining W Nicholas WN McConkey Marie E ME Habib Naomi N Yosef Nir N Chang Cindy Y CY Shay Tal T Frampton Garrett M GM Drake Adam C B AC Leskov Ilya I Nilsson Bjorn B Preffer Fred F Dombkowski David D Evans John W JW Liefeld Ted T Smutko John S JS Chen Jianzhu J Friedman Nir N Young Richard A RA Golub Todd R TR Regev Aviv A Ebert Benjamin L BL

Cell 20110101 2

Though many individual transcription factors are known to regulate hematopoietic differentiation, major aspects of the global architecture of hematopoiesis remain unknown. Here, we profiled gene expression in 38 distinct purified populations of human hematopoietic cells and used probabilistic models of gene expression and analysis of cis-elements in gene promoters to decipher the general organization of their regulatory circuitry. We identified modules of highly coexpressed genes, some of which ...[more]

PMID: 21241896

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Project description:Transcriptome analysis of adult hematopoietic stem cells (HSC) and their progeny has informed our understanding of blood differentiation and leukemogenesis, but a similarly transformative analysis of the embryonic origins of hematopoiesis is lacking. To address this issue, we acquired gene expression profiles of developing HSC purified from over 2500 dissected murine embryos and adult mice, and applied a network biology-based analysis to reconstruct the gene regulatory networks of sequential stages of HSC development. We found that embryonic hematopoietic elements clustered into three distinct transcriptional states characteristic of the definitive yolk sac, HSCs emerging from hemogenic endothelium, and definitive HSCs. We functionally validated several candidate transcriptional regulators of HSC ontogeny by morpholino-mediated knock-down in zebrafish embryos, confirming changes in the expression of HSC markers runx1 and c-myb in the aorta-gonads-mesonephros (AGM), the site of definitive HSC specification. Moreover, we found that HSCs derived from differentiating embryonic stem cells in vitro (ESC-HSC) most closely resemble definitive HSC, yet lack a signature indicative of specification by Notch signaling, which likely accounts for their deficient lymphoid development. Our analysis and accompanying web resource will accelerate the characterization of regulators of HSC ontogeny, facilitate efforts to direct hematopoietic differentiation and cell fate conversion, and serve as a model to study the origins of other adult stem cells. Hematopoietic stem cells and their precursors were isolated from mouse embryos and distinct stages and sites during development, purified by fluorescence activated cell sorting, and gene expression profiled on Affymetrix arrays. We also profiled HSCs and their precurors derived by in vitro differentitation of embryonic stem cells [expression data from GSE16925 and GSE14012 was used for mESCs, available at http://hsc.hms.harvard.edu/].

Dataset Information

Densely interconnected transcriptional circuits control cell states in human hematopoiesis

Publications

Densely interconnected transcriptional circuits control cell states in human hematopoiesis.

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