Transposable elements are DNA sequences that can move from one location to another in the genome. These seemingly nonfunctional sequences have been termed junk DNA, although Barbara McClintock, Ph.D., who received the Nobel Prize for their discovery in 1983, called them controlling elements.
Transposable elements, or TEs, were the focus of a June 7 Keystone Science Seminar by Ting Wang, Ph.D., from Washington University in St. Louis. He presented research that demonstrated the integral roles of TEs in gene regulation and evolution of the epigenome. The epigenome includes chemical signals that attach to DNA and modify its function, without changing the DNA itself.
Wang explained epigenetics by likening the human genome to a collection of books. “Everyone has their own set of books. Even with the same set of books, there are many ways of reading them,” Wang said. Epigenetics is the study of how different cells read the same book differently.
The talk was hosted by Fred Tyson, Ph.D., from the NIEHS Division of Extramural Research and Training. The two scientists met while they both were involved in the Roadmap Epigenomics Mapping Consortium, a National Institutes of Health-funded program to characterize epigenomic landscapes of human tissues and cells.
Role in evolution of gene regulatory networks
Wang’s lab has studied how TEs influence the development of gene regulatory networks. These networks include target genes of transcriptional factors, which are controlled through binding sites. Transcriptional factors are proteins involved in the process of converting, or transcribing, DNA into messenger RNA. A collection of genes may be regulated by a transcriptional factor in response to environmental cues.
“TEs can make copies of themselves, jump around, and disperse the transcriptional factor binding sites throughout the genome and efficiently create a co-regulation relationship,” Wang explained. As an example, he discussed the tumor suppressor protein p53, a master regulator that activates genes involved in cell cycles and stress-induced cell death.
“Fifty percent of human tumors contain a single point mutation in the DNA-binding domain of p53,” Wang said, describing the protein’s significance in cancer. His study found that nearly one-third of p53 sites overlap with a subclass of TEs derived from retroviruses, known as endogenous retrovirus sequences.
Wang’s recent work, mapping the binding sites for 26 transcriptional factors, showed that TEs contributed to one-fifth of those binding sites, although the distribution of the sites varies greatly in the mouse and human genomes.
Because of that variation, a question about the usefulness of mice and other model organisms was raised by NIEHS Deputy Director Rick Woychik, Ph.D., after the seminar. Wang emphasized the need to acknowledge differences when interpreting data, but he also distinguished the differences between gene sequence and gene function. “The core of gene regulatory function is maintained [across species],” he said.
TE methylation depends on cell type
For the Roadmap project, Wang’s lab developed an epigenome browser, which allows scientists to map and integrate genomic data from many tissues and cell types. Wang’s group has mapped the DNA methylation of TEs across the human genome. They observed methylation levels that varied according to tissue, cell type, developmental status, and disease state.
“During the development of specific cells or tissues, TEs are epigenetically changed,” Wang said. Exploring these cell type-specific methylation patterns may help identify cell lineage, or even characterize cancer.
(Qing Xu is a biologist in the NIEHS Metabolism, Genes, and Environment Group.)