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.
Bibliographical noteFunding 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.