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Cell Syst. 2018 Mar 28;6(3):381-394.e7. doi: 10.1016/j.cels.2018.01.002. Epub 2018 Feb 14.

Comparative Analysis of Immune Cells Reveals a Conserved Regulatory Lexicon.

Author information

1
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
2
Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
3
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Bioinformatics Core, University of Massachusetts Medical School, Worcester, MA 01605, USA.
5
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
6
Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA.
7
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: jeremy.luban@umassmed.edu.
8
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Bioinformatics Core, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: manuel.garber@umassmed.edu.

Abstract

Most well-characterized enhancers are deeply conserved. In contrast, genome-wide comparative studies of steady-state systems showed that only a small fraction of active enhancers are conserved. To better understand conservation of enhancer activity, we used a comparative genomics approach that integrates temporal expression and epigenetic profiles in an innate immune system. We found that gene expression programs diverge among mildly induced genes, while being highly conserved for strongly induced genes. The fraction of conserved enhancers varies greatly across gene expression programs, with induced genes and early-response genes, in particular, being regulated by a higher fraction of conserved enhancers. Clustering of conserved accessible DNA sequences within enhancers resulted in over 60 sequence motifs including motifs for known factors, as well as many with unknown function. We further show that the number of instances of these motifs is a strong predictor of the responsiveness of a gene to pathogen detection.

KEYWORDS:

comparative genomics; enhancers; gene regulation; innate immunity; toll-like receptors

PMID:
29454939
PMCID:
PMC5876141
DOI:
10.1016/j.cels.2018.01.002
[Indexed for MEDLINE]
Free PMC Article

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