Densely interconnected transcriptional circuits control cell states in human hematopoiesis

Noa Novershtern; Aravind Subramanian; Lee N. Lawton; Raymond H. Mak; W. Nicholas Haining; Marie E. McConkey; Naomi Habib; Nir Yosef; Cindy Y. Chang; Tal Shay; Garrett M. Frampton; Adam C.B. Drake; Ilya Leskov; Bjorn Nilsson; Fred Preffer; David Dombkowski; John W. Evans; Ted Liefeld; John S. Smutko; Jianzhu Chen; Nir Friedman; Richard A. Young; Todd R. Golub; Aviv Regev; Benjamin L. Ebert

doi:10.1016/j.cell.2011.01.004

Densely interconnected transcriptional circuits control cell states in human hematopoiesis

Noa Novershtern, Aravind Subramanian, Lee N. Lawton, Raymond H. Mak, W. Nicholas Haining, Marie E. McConkey, Naomi Habib, Nir Yosef, Cindy Y. Chang, Tal Shay, Garrett M. Frampton, Adam C.B. Drake, Ilya Leskov, Bjorn Nilsson, Fred Preffer, David Dombkowski, John W. Evans, Ted Liefeld, John S. Smutko, Jianzhu ChenNir Friedman, Richard A. Young, Todd R. Golub, Aviv Regev^*, Benjamin L. Ebert

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

742 Scopus citations

Abstract

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 are restricted to a single lineage but most of which 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. These findings suggest a more complex regulatory system for hematopoiesis than previously assumed.

Original language	English
Pages (from-to)	296-309
Number of pages	14
Journal	Cell
Volume	144
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2011.01.004
State	Published - 21 Jan 2011

Bibliographical note

Funding Information:
We thank E. Lander, I. Amit, and I. Gat-Viks for critical review of the manuscript; D. Scadden for helpful discussions; L. Gaffney and S. Hart for assistance with figure generation; and D. Peck, J. Lamb, R. Onofrio, and the Broad Genetic Analysis Platform for assistance with expression arrays. The work was funded by the NIH (grants R01 HL082945 and P01 CA108631 to B.L.E. and the PIONEER award to A.R.), the Burroughs-Wellcome Fund (CAMS to B.L.E. and CASI to A.R.), funds from Landon and Lavinia Clay (R.A.Y.) and HHMI (T.R.G. and A.R.). A.R. is an investigator of the Merkin Foundation for Stem Cell Research at the Broad Institute. J.S.S. is an employee of NuGEN Technologies, Inc.

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Novershtern, N., Subramanian, A., Lawton, L. N., Mak, R. H., Haining, W. N., McConkey, M. E., Habib, N., Yosef, N., Chang, C. Y., Shay, T., Frampton, G. M., Drake, A. C. B., Leskov, I., Nilsson, B., Preffer, F., Dombkowski, D., Evans, J. W., Liefeld, T., Smutko, J. S., ... Ebert, B. L. (2011). Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell, 144(2), 296-309. https://doi.org/10.1016/j.cell.2011.01.004

@article{45e1bd4e2de94a088848e1efaaa65934,

title = "Densely interconnected transcriptional circuits control cell states in human hematopoiesis",

abstract = "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 are restricted to a single lineage but most of which 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. These findings suggest a more complex regulatory system for hematopoiesis than previously assumed.",

author = "Noa Novershtern and Aravind Subramanian and Lawton, {Lee N.} and Mak, {Raymond H.} and Haining, {W. Nicholas} and McConkey, {Marie E.} and Naomi Habib and Nir Yosef and Chang, {Cindy Y.} and Tal Shay and Frampton, {Garrett M.} and Drake, {Adam C.B.} and Ilya Leskov and Bjorn Nilsson and Fred Preffer and David Dombkowski and Evans, {John W.} and Ted Liefeld and Smutko, {John S.} and Jianzhu Chen and Nir Friedman and Young, {Richard A.} and Golub, {Todd R.} and Aviv Regev and Ebert, {Benjamin L.}",

note = "Funding Information: We thank E. Lander, I. Amit, and I. Gat-Viks for critical review of the manuscript; D. Scadden for helpful discussions; L. Gaffney and S. Hart for assistance with figure generation; and D. Peck, J. Lamb, R. Onofrio, and the Broad Genetic Analysis Platform for assistance with expression arrays. The work was funded by the NIH (grants R01 HL082945 and P01 CA108631 to B.L.E. and the PIONEER award to A.R.), the Burroughs-Wellcome Fund (CAMS to B.L.E. and CASI to A.R.), funds from Landon and Lavinia Clay (R.A.Y.) and HHMI (T.R.G. and A.R.). A.R. is an investigator of the Merkin Foundation for Stem Cell Research at the Broad Institute. J.S.S. is an employee of NuGEN Technologies, Inc. ",

year = "2011",

month = jan,

day = "21",

doi = "10.1016/j.cell.2011.01.004",

language = "אנגלית",

volume = "144",

pages = "296--309",

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Novershtern, N, Subramanian, A, Lawton, LN, Mak, RH, Haining, WN, McConkey, ME, Habib, N, Yosef, N, Chang, CY, Shay, T, Frampton, GM, Drake, ACB, Leskov, I, Nilsson, B, Preffer, F, Dombkowski, D, Evans, JW, Liefeld, T, Smutko, JS, Chen, J, Friedman, N, Young, RA, Golub, TR, Regev, A & Ebert, BL 2011, 'Densely interconnected transcriptional circuits control cell states in human hematopoiesis', Cell, vol. 144, no. 2, pp. 296-309. https://doi.org/10.1016/j.cell.2011.01.004

TY - JOUR

T1 - Densely interconnected transcriptional circuits control cell states in human hematopoiesis

AU - Novershtern, Noa

AU - Subramanian, Aravind

AU - Lawton, Lee N.

AU - Mak, Raymond H.

AU - Haining, W. Nicholas

AU - McConkey, Marie E.

AU - Habib, Naomi

AU - Yosef, Nir

AU - Chang, Cindy Y.

AU - Shay, Tal

AU - Frampton, Garrett M.

AU - Drake, Adam C.B.

AU - Leskov, Ilya

AU - Nilsson, Bjorn

AU - Preffer, Fred

AU - Dombkowski, David

AU - Evans, John W.

AU - Liefeld, Ted

AU - Smutko, John S.

AU - Chen, Jianzhu

AU - Friedman, Nir

AU - Young, Richard A.

AU - Golub, Todd R.

AU - Regev, Aviv

AU - Ebert, Benjamin L.

N1 - Funding Information: We thank E. Lander, I. Amit, and I. Gat-Viks for critical review of the manuscript; D. Scadden for helpful discussions; L. Gaffney and S. Hart for assistance with figure generation; and D. Peck, J. Lamb, R. Onofrio, and the Broad Genetic Analysis Platform for assistance with expression arrays. The work was funded by the NIH (grants R01 HL082945 and P01 CA108631 to B.L.E. and the PIONEER award to A.R.), the Burroughs-Wellcome Fund (CAMS to B.L.E. and CASI to A.R.), funds from Landon and Lavinia Clay (R.A.Y.) and HHMI (T.R.G. and A.R.). A.R. is an investigator of the Merkin Foundation for Stem Cell Research at the Broad Institute. J.S.S. is an employee of NuGEN Technologies, Inc.

PY - 2011/1/21

Y1 - 2011/1/21

N2 - 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 are restricted to a single lineage but most of which 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. These findings suggest a more complex regulatory system for hematopoiesis than previously assumed.

AB - 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 are restricted to a single lineage but most of which 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. These findings suggest a more complex regulatory system for hematopoiesis than previously assumed.

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SN - 0092-8674

VL - 144

SP - 296

EP - 309

JO - Cell

JF - Cell

IS - 2

ER -

Densely interconnected transcriptional circuits control cell states in human hematopoiesis

Abstract

Bibliographical note

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