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

Charles G. Danko, Lauren A. Choate, Brooke A. Marks, Edward J. Rice, Zhong Wang, Tinyi Chu, Andre L. Martins, Noah Dukler, Scott A. Coonrod, Elia D. Tait Wojno, John T. Lis, W. Lee Kraus, Adam Siepel

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)537-548
Number of pages12
JournalNature Ecology and Evolution
Volume2
Issue number3
DOIs
StatePublished - Mar 1 2018

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Ecology

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