MiDReG: A method of mining developmentally regulated genes using Boolean implications
- Debashis Sahooa,b,
- Jun Seitab,
- Deepta Bhattacharyab,2,
- Matthew A. Inlayb,
- Irving L. Weissmanb,
- Sylvia K. Plevritisc, and
- David L. Dilld,1
- aDepartment of Electrical Engineering, Stanford University, Stanford, CA, 94305;
- bInstitute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, CA, 94305;
- cDepartment of Radiology, Stanford University, CA, 94305; and
- dDepartment of Computer Science, Stanford University, CA, 94305
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Contributed by Irving L Weissman, December 22, 2009 (sent for review September 10, 2009)
Abstract
We present a method termed mining developmentally regulated genes (MiDReG) to predict genes whose expression is either activated or repressed as precursor cells differentiate. MiDReG does not require gene expression data from intermediate stages of development. MiDReG is based on the gene expression patterns between the initial and terminal stages of the differentiation pathway, coupled with “if-then” rules (Boolean implications) mined from large-scale microarray databases. MiDReG uses two gene expression-based seed conditions that mark the initial and the terminal stages of a given differentiation pathway and combines the statistically inferred Boolean implications from these seed conditions to identify the relevant genes. The method was validated by applying it to B-cell development. The algorithm predicted 62 genes that are expressed after the KIT+ progenitor cell stage and remain expressed through CD19+ and AICDA+ germinal center B cells. qRT-PCR of 14 of these genes on sorted B-cell progenitors confirmed that the expression of 10 genes is indeed stably established during B-cell differentiation. Review of the published literature of knockout mice revealed that of the predicted genes, 63.4% have defects in B-cell differentiation and function and 22% have a role in the B cell according to other experiments, and the remaining 14.6% are not characterized. Therefore, our method identified novel gene candidates for future examination of their role in B-cell development. These data demonstrate the power of MiDReG in predicting functionally important intermediate genes in a given developmental pathway that is defined by a mutually exclusive gene expression pattern.
Footnotes
- 1To whom correspondence should be addressed. E-mail: dill{at}cs.stanford.edu.
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Author contributions: D.S. designed research; D.S., J.S., D.B., M.A.I., and D.L.D. performed research; D.S. and D.L.D. contributed new reagents/analytic tools; D.S., J.S., D.B., M.A.I., I.L.W., S.K.P., and D.L.D. analyzed data; and D.S., J.S., D.B., M.A.I., I.L.W., S.K.P., and D.L.D. wrote the paper. D.S. and D.L.D. designed MiDReG. D.S., J.S., D.B., and M.A.I. validated MiDReG for B-cell development. S.K.P. helped conceptualize the direction of the MiDReG project.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0913635107/DCSupplemental.
