Epigenetic modifications are associated with inter-species gene expression variation in primates.

Xiang Zhou,Marsha Myrthil,Yoav Gilad,Jonathan K Pritchard,Noah Lewellen,Katelyn Michelini,Emily R Davenport,Carolyn E Cain,Matthew Stephens

doi:10.1186/s13059-014-0547-3

Abstract

BackgroundChanges in gene regulation have long been thought to play an important role in evolution and speciation, especially in primates. Over the past decade, comparative genomic studies have revealed extensive inter-species differences in gene expression levels, yet we know much less about the extent to which regulatory mechanisms differ between species.ResultsTo begin addressing this gap, we perform a comparative epigenetic study in primate lymphoblastoid cell lines, to query the contribution of RNA polymerase II and four histone modifications, H3K4me1, H3K4me3, H3K27ac, and H3K27me3, to inter-species variation in gene expression levels. We find that inter-species differences in mark enrichment near transcription start sites are significantly more often associated with inter-species differences in the corresponding gene expression level than expected by chance alone. Interestingly, we also find that first-order interactions among the five marks, as well as chromatin states, do not markedly contribute to the degree of association between the marks and inter-species variation in gene expression levels, suggesting that the marginal effects of the five marks dominate this contribution.ConclusionsOur observations suggest that epigenetic modifications are substantially associated with changes in gene expression levels among primates and may represent important molecular mechanisms in primate evolution.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0547-3) contains supplementary material, which is available to authorized users.

Highlights

Changes in gene regulation have long been thought to play an important role in evolution and speciation, especially in primates
Genome-wide profiling of Pol RNA polymerase II (II), four histone marks, and mRNA We used chromatin immunoprecipitation (ChIP) followed by massively parallel sequencing (ChIPseq) to identify genomic regions associated with polymerase II (Pol II) as well as with four histone modifications (H3K4me1, H3K4me3, H3K27ac, and H3K27me3) in lymphoblastoid cell lines (LCLs) from eight individuals from each of the three primate species, humans, chimpanzees, and rhesus macaques
In order to analyze our data in a broader context, we considered 15 different chromatin state annotations previously identified in LCLs in the human genome [33,58]

Summary

Introduction

Changes in gene regulation have long been thought to play an important role in evolution and speciation, especially in primates. The present study aims to take another step towards understanding gene regulatory evolution in primates, by focusing on inter-species differences in epigenetic regulatory mechanisms that are functionally associated with the regulation of transcription initiation. By studying a number of regulatory mechanisms in parallel in multiple primate species, we can assess the extent to which such differences are associated with inter-species variation in gene expression levels. Transcription of mRNA is preceded by the assembly of large protein complexes that coordinate the recruitment, initiation, and elongation of RNA polymerase II (Pol II) [29] Of these large protein complexes relies on epigenetic information, including various histone modifications [30], to provide an additional layer of targets for regulatory proteins, and to directly affect chromatin accessibility of the promoter region to DNA-binding proteins [31]. Pol II occupancy and abundance of histone modifications are highly predictive of gene expression levels in multiple cell types [27,32,33,34,35]

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