The epigenomic landscape of transposable elements across normal human development and anatomy

Abstract

Transposable elements (TEs) have deposited functional regulatory elements throughout the human genome. Although most are silenced, certain TEs have been co-opted by the host. However, a comprehensive, multidimensional picture of the contribution of TEs to normal human gene regulation is still lacking. Here, we quantify the epigenomic status of TEs across human anatomy and development using data from the Roadmap Epigenomics Project. We find that TEs encompass a quarter of the human regulatory epigenome, and 47% of elements can be in an active regulatory state. We demonstrate that SINEs are enriched relative to other classes for active and transcribed marks, that TEs encompass a higher proportion of enhancer states in the hematopoietic lineage, and that DNA methylation of Alu elements decreases with age, corresponding with a loss of CpG islands. Finally, we identify TEs that may perform an evolutionarily conserved regulatory function, providing a systematic profile of TE activity in normal human tissue.

Transposable elements as a potent source of diverse cis -regulatory sequences in mammalian genomes

“…Across the 127 human cell and tissue samples, almost half the TEs have a signature of putative active regulatory state in at least one of the analysed cell types. Interestingly, although TEs represent a significant fraction of regulatory and transcribed chromatin states across all epigenomes, in a given epigenome TEs are relatively depleted in active states, as most are silenced [40,41].…”

“…Despite the key contribution of TEs to species-specific enhancers, in most mouse and human tissues TEs enriched for enhancer signatures are mostly 'older' than non-regulatory genomic TEs [40,41]. This suggests that mutations that occurred over evolutionary times allowed individual insertions within specific TE subclasses to acquire mutations facilitating gain of enhancer function ( figure 1a).…”

Functional characterization of thousands of type 2 diabetes-associated and chromatin-modulating variants under steady state and endoplasmic reticulum stress

“…The MPRA results obtained in this study thus suggest that repetitive element-containing sequences may play important roles in modulating stimulus and/or stress-responsive ß cell transcriptional programs and remind us to consider the potentially important roles that repetitive elements, and SNPs within them, may play in the genetics of islet (dys)function, diabetes risk and progression. Studies over the past few years demonstrating repetitive element-mediated oncogene activation and modulation of chromatin structure have contributed to an emerging appreciation of the importance of these sequences in epigenetic and transcriptional regulation 55–63 . Recently, Hernandez et al found that Alu elements are transcriptionally induced by cellular stress, including thermal and ER stress, and that the corresponding SINE RNAs function as critical transcriptional switches during stress 64 .…”

Host Gene Regulation by Transposable Elements: The New, the Old and the Ugly

“…Similarly, upregulation of HERVK in pluripotent cells has been reported [ 64 , 72 ]. Notable studies have documented how TEs may regulate human genes in adult tissues, for example in CD4 + T cells and macrophages [ 68 , 73 , 74 , 75 , 76 ]. Still relatively little is known, however, about how the ever-evolving TE burden contributes to present-day human gene regulatory networks.…”