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Nature. 2014 Nov 20;515(7527):371-375. doi: 10.1038/nature13985.

Principles of regulatory information conservation between mouse and human.

Author information

1
Department of Genetics, Stanford University, Stanford, CA 94305, USA.
2
Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
3
Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA 16802, USA.
4
Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108, USA.
5
Division of Cardiovascular Medicine, Stanford University, Stanford, CA 94304, USA.
6
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
7
Lawrence Berkeley National Laboratory, Genomics Division, Berkeley, CA 94701,USA.
8
Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA.
9
School of Natural Sciences, University of California, Merced, CA 95343,USA.
#
Contributed equally

Abstract

To broaden our understanding of the evolution of gene regulation mechanisms, we generated occupancy profiles for 34 orthologous transcription factors (TFs) in human-mouse erythroid progenitor, lymphoblast and embryonic stem-cell lines. By combining the genome-wide transcription factor occupancy repertoires, associated epigenetic signals, and co-association patterns, here we deduce several evolutionary principles of gene regulatory features operating since the mouse and human lineages diverged. The genomic distribution profiles, primary binding motifs, chromatin states, and DNA methylation preferences are well conserved for TF-occupied sequences. However, the extent to which orthologous DNA segments are bound by orthologous TFs varies both among TFs and with genomic location: binding at promoters is more highly conserved than binding at distal elements. Notably, occupancy-conserved TF-occupied sequences tend to be pleiotropic; they function in several tissues and also co-associate with many TFs. Single nucleotide variants at sites with potential regulatory functions are enriched in occupancy-conserved TF-occupied sequences.

PMID:
25409826
PMCID:
PMC4343047
DOI:
10.1038/nature13985
[Indexed for MEDLINE]
Free PMC Article

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