Dynamic evolution of regulatory element ensembles in primate CD4(+) T cells

Danko, C. G., Choate, L. A., Marks, B. A., Rice, E. J., Wang, Z., Chu, T., Martins, A. L., Dukler, N., Coonrod, S. A., Tait Wojno, E. D., Lis, J. T., Kraus, W. L., Siepel, A. (January 2018) Dynamic evolution of regulatory element ensembles in primate CD4(+) T cells. Nat Ecol Evol. ISSN 2397-334x

URL: https://www.ncbi.nlm.nih.gov/pubmed/29379187
DOI: 10.1038/s41559-017-0447-5

Abstract

How evolutionary changes at enhancers affect the transcription of target genes remains an important open question. Previous comparative studies of gene expression have largely measured the abundance of messenger RNA, which is affected by post-transcriptional regulatory processes, hence limiting inferences about the mechanisms underlying expression differences. Here, we directly measured nascent transcription in primate species, allowing us to separate transcription from post-transcriptional regulation. We used precision run-on and sequencing to map RNA polymerases in resting and activated CD4(+) T cells in multiple human, chimpanzee and rhesus macaque individuals, with rodents as outgroups. We observed general conservation in coding and non-coding transcription, punctuated by numerous differences between species, particularly at distal enhancers and non-coding RNAs. Genes regulated by larger numbers of enhancers are more frequently transcribed at evolutionarily stable levels, despite reduced conservation at individual enhancers. Adaptive nucleotide substitutions are associated with lineage-specific transcription and at one locus, SGPP2, we predict and experimentally validate that multiple substitutions contribute to human-specific transcription. Collectively, our findings suggest a pervasive role for evolutionary compensation across ensembles of enhancers that jointly regulate target genes.

Item Type: Paper
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells
organs, tissues, organelles, cell types and functions > cell types and functions > cell types > T cells

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > cis-regulatory elements
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene regulation
CSHL Authors:
Communities: CSHL labs > Siepel lab
CSHL Cancer Center Program > Cancer Genetics
Depositing User: Matt Covey
Date: 29 January 2018
Date Deposited: 05 Feb 2018 17:27
Last Modified: 12 Jun 2018 16:04
PMCID: PMC5957490
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36058

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