Latent Regulatory Potential of Human-Specific Repetitive Elements

Michelle C Ward,Michael D Wilson,Nuno L Barbosa-Morais,Dominic Schmidt,Rory Stark,Qun Pan,Petra C Schwalie,Suraj Menon,Margus Lukk,Stephen Watt,David Thybert,Claudia Kutter,Kristina Kirschner,Paul Flicek,Benjamin J Blencowe,Duncan T Odom

doi:10.1016/j.molcel.2012.11.013

Abstract

SummaryAt least half of the human genome is derived from repetitive elements, which are often lineage specific and silenced by a variety of genetic and epigenetic mechanisms. Using a transchromosomic mouse strain that transmits an almost complete single copy of human chromosome 21 via the female germline, we show that a heterologous regulatory environment can transcriptionally activate transposon-derived human regulatory regions. In the mouse nucleus, hundreds of locations on human chromosome 21 newly associate with activating histone modifications in both somatic and germline tissues, and influence the gene expression of nearby transcripts. These regions are enriched with primate and human lineage-specific transposable elements, and their activation corresponds to changes in DNA methylation at CpG dinucleotides. This study reveals the latent regulatory potential of the repetitive human genome and illustrates the species specificity of mechanisms that control it.

Highlights

Between one-half and possibly up to two-thirds of the human genome is derived from repetitive sequences, most of which are classified as transposable elements (TEs)
Many HsChr21 Regions Transcriptionally Active in Tc1 Mouse Tissues Are Silent in Human To compare in vivo gene regulation of both repetitive and nonrepetitive regions of HsChr21 between human and Tc1 mouse livers, we experimentally profiled the following using highthroughput sequencing methodologies: (1) polyadenylated-containing mRNA transcripts, (2) regions enriched for trimethylation of H3K4 (H3K4me3) as a marker for transcriptional initiation (Bernstein et al, 2005; Guenther et al, 2007; Heintzman et al, 2007), and (3) genomic occupancy of the RNA polymerase II (Pol II) basal machinery (Figure 1; Experimental Procedures; see Table S1A, Document S2, and Figure S1 online)
Using H3K4me3 as a proxy for transcription initiation, we found that most regions activated on HsChr21 (214/383) were not significantly different in quality and quantity between the two species

Summary

Introduction

Between one-half and possibly up to two-thirds of the human genome is derived from repetitive sequences, most of which are classified as transposable elements (TEs) (de Koning et al, 2011). TEs can serve as regulatory DNA contributing to tissuespecific transcriptional evolution (Bourque et al, 2008; Faulkner et al, 2009; Lowe et al, 2007; Oliver and Greene, 2009), and their activity has altered the regulatory circuitry of embryonic stem cells (Kunarso et al, 2010), mammalian pregnancy pathways (Lynch et al, 2011; Xie et al, 2010), and the deployment of CTCF binding sites across mammalian genomes (Bourque et al, 2008; Schmidt et al, 2012). As transposons rapidly acquire mutations and as their activity can damage a genome, multiple mechanisms have evolved to silence them in mammals (Levin and Moran, 2011), including specific histone modifications, DNA methylation, and targeted small RNAs (De Fazio et al, 2011; Maksakova et al, 2008; Rebollo et al, 2011; Reuter et al, 2011)

Results

Discussion

Conclusion