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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., Although most are silenced, certain transposable elements (TEs) have been co-opted by the host. Here, the authors quantify the epigenomic status of TEs using data from the Roadmap Epigenomics Project, provide a systematic profile of TE activity across normal human tissues and development, finding that TEs encompass a quarter of the human regulatory epigenome, with 47% of TEs in regulatory states.

Eukaryotic gene regulation is mediated by cis -regulatory elements, which are embedded within the vast non-coding genomic space and recognized by the transcription factors in a sequence- and context-dependent manner. A large proportion of eukaryotic genomes, including at least half of the human genome, are composed of transposable elements (TEs), which in their ancestral form carried their own cis -regulatory sequences able to exploit the host trans environment to promote TE transcription and facilitate transposition. Although not all present-day TE copies have retained this regulatory function, the preexisting regulatory potential of TEs can provide a rich source of cis -regulatory innovation for the host. Here, we review recent evidence documenting diverse contributions of TE sequences to gene regulation by functioning as enhancers, promoters, silencers and boundary elements. We discuss how TE-derived enhancer sequences can rapidly facilitate changes in existing gene regulatory networks and mediate species- and cell-type-specific regulatory innovations, and we postulate a unique contribution of TEs to species-specific gene expression divergence in pluripotency and early embryogenesis. With advances in genome-wide technologies and analyses, systematic investigation of TEs' cis -regulatory potential is now possible and our understanding of the biological impact of genomic TEs is increasing. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

Aberrant DNA hypomethylation may play an important role in the growth rate of glioblastoma (GBM), but the functional impact on transcription remains poorly understood. We assayed the GBM methylome with MeDIP-seq and MRE-seq, adjusting for copy number differences, in a small set of non-glioma CpG island methylator phenotype (non-G-CIMP) primary tumors. Recurrent hypomethylated loci were enriched within a region of chromosome 5p15 that is specified as a cancer amplicon and also encompasses TERT, encoding telomerase reverse transcriptase, which plays a critical role in tumorigenesis. Overall, 76 gene body promoters were recurrently hypomethylated, including TERT and the oncogenes GLI3 and TP73. Recurring hypomethylation also affected previously unannotated alternative promoters, and luciferase reporter assays for three of four of these promoters confirmed strong promoter activity in GBM cells. Histone H3 lysine 4 trimethylation (H3K4me3) ChIP-seq on tissue from the GBMs uncovered peaks that coincide precisely with tumor-specific decrease of DNA methylation at 200 loci, 133 of which are in gene bodies. Detailed investigation of TP73 and TERT gene body hypomethylation demonstrated increased expression of corresponding alternate transcripts, which in TP73 encodes a truncated p73 protein with oncogenic function and in TERT encodes a putative reverse transcriptase-null protein. Our findings suggest that recurring gene body promoter hypomethylation events, along with histone H3K4 trimethylation, alter the transcriptional landscape of GBM through the activation of a limited number of normally silenced promoters within gene bodies, in at least one case leading to expression of an oncogenic protein.

Transposable elements (TEs) are no longer considered to be ‘junk’ DNA. Here, we review how TEs can impact gene regulation systematically. TEs encode various regulatory elements that enables them to regulate gene expression. RJ Britten and EH Davidson hypothesised that TEs can integrate the function of various transcriptional regulators into gene regulatory networks. Uniquely TEs can deposit regulatory sites across the genome when they transpose, and thereby bring multiple genes under control of the same regulatory logic. Several studies together have robustly established that TEs participate in embryonic development, and oncogenesis. We discuss the regulatory characteristics of TEs in context of evolution to understand the extent of their impact on gene networks. Understanding these features of TEs is central to future investigations of TEs in cellular processes and phenotypic presentations, which are applicable to development and disease studies. We re-visit the Britten-Davidson ‘gene-battery’ model and understand the genetic and transcriptional impact of TEs in innovating gene regulatory networks.

To broaden our understanding of the evolution of gene regulation mechanisms, we generated occupancy profiles for 34 orthologous transcription factors (TFs) in human-mouse erythroid progenitor, lymphoblast and embryonic stem-cell lines. By combining the genome-wide transcription factor occupancy repertoires, associated epigenetic signals, and co-association patterns, here we deduce several evolutionary principles of gene regulatory features operating since the mouse and human lineages diverged. The genomic distribution profiles, primary binding motifs, chromatin states, and DNA methylation preferences are well conserved for TF-occupied sequences. However, the extent to which orthologous DNA segments are bound by orthologous TFs varies both among TFs and with genomic location: binding at promoters is more highly conserved than binding at distal elements. Notably, occupancy-conserved TF-occupied sequences tend to be pleiotropic; they function in several tissues and also co-associate with many TFs. Single nucleotide variants at sites with potential regulatory functions are enriched in occupancy-conserved TF-occupied sequences.

Carcinogenesis results from aberrations in gene regulatory networks at the genetic and epigenetic levels. Epigenetic changes such as global hypomethylation along with hypermethylated tumor-suppressor gene promoters are hallmarks of many cancers. Transposable elements (TEs) constitute the majority of non-coding sequence in the human genome and 50% of the total human genome sequence; they are thought to be suppressed by DNA methylation in somatic tissues. TEs often carry transcription factor binding sites and can function as transcriptional enhancers. Mis-regulation of DNA methylation can lead to abnormal gene activity from TE-based enhancers. Although many studies have profiled cancer DNA methylomes, there has not been a focused study to investigate the changes in TE DNA methylation in cancer and its effect on cancer gene expression. We hypothesize that mis-expression of genes from TE-based enhancers contributes to carcinogenesis. To test this hypothesis, we generated complete DNA methylomes of endometrial cancer samples and the matched normal tissue. We then used computational algorithms to identify differentially methylated transposon subfamilies. Our approach consists of using two complementary sequencing-based methods to map the DNA methylomes (MeDIP-seq and MRE-seq). To map unmethylated sites at single CpG resolution, we sequence DNA, digested by three methylation-sensitive restriction enzymes (MRE). We use the HpaII (C^CGG), Hin6I (G^CGC) and AciI (C^CGC) enzymes to access a very large fraction of potentially non-methylated CpG sites. In addition, to map methylated regions we use an anti-methylcytosine antibody to immunoprecipitate the methylated fraction of DNA fragments and then sequence them. Analyses of sequencing data, generally discards reads that map to repetitive regions in the genome, thus significantly reducing our ability to investigate TEs. Our computational approach, harnesses reads that map to repetitive regions by re-aligning them to TE subfamilies. We then measure the enrichment of reads for each TE subfamily from both the sequencing methods, in the cancer tissue compared to the matched normal tissue. Our findings reveal that, as expected, TEs in normal endometrial tissues are mostly methylated. However, contrary to the common belief, we found that majority of TEs remain methylated in endometrial cancer samples. A few dozen TE subfamilies, including several ERV/LTR subfamilies (endogeneous retrovirus) are demethylated. More interestingly, when we compare our three type I cancer samples with the three type II cancer samples, we detect a clear cancer type-specific, TE-subfamily-specific DNA demethylation pattern. This observation, coupled with the idea that different TE subfamilies may encode different enhancer elements, suggests that demethylated TEs may rewire cancer type-specific gene regulatory networks and contribute to cancer-specific phenotypes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-379. doi:1538-7445.AM2012-LB-379