At least half of the human genome is derived from transposable elements (TEs). These highly repetitive elements often harbor transcription factor binding sites and epigenetic regulatory signals. TEs have shaped gene regulatory networks during evolution and are often dysregulated in diseases. However, the extent to which TEs contribute sequences to functional regulatory networks, and how TE sequences evolved from parasitic DNA to functional elements, remains unclear. Answering these questions will expand our understanding of regulatory networks by including the contributions of TEs to genome-wide patterns of gene regulation. In this proposal, we introduce a novel strategy that combines computational prediction of TE derived cell type-specific enhancers with massively parallel reporter gene assays to understand the impact of TEs to cell type-specific gene regulation.
In Specific Aim 1 we plan to develop an epigenomics-based approach to detect TE-derived enhancers and their target genes. We will then test their regulatory activities using CRE-seq, a massive parallel reporter gene assay. We will bring to bear computational models that allow us to predict TE-derived enhancers. If successful, not only will we produce the largest catalog of TE-derived cell type-specific enhancers, but also we will have created a robust framework for detecting the contributions of TEs to gene regulation in any cell type or tissue.
In Specific Aim 2 we will develop a phylogenetically informed functional association assay. We will reconstruct sequences representing the evolutionary intermediates of candidate TEs and test the regulatory activities of these sequences with CRE-seq. We will address questions including whether particular classes of TEs gained TF-binding sites and then spread quickly, or whether TEs first spread and later gained TF binding sites. If successful, we will develop an understanding of what sequence features drive the functional potential of TEs, and the modes of evolution followed by different families of TEs during regulatory network evolution. Such an understanding will dramatically improve our picture of gene regulatory network evolution by including the effects of TEs, a major class of fast evolving regulatory sequences that have been largely ignored in functional genomics studies. The methods developed in this proposal will have a high impact on the utility of data produced by consortia such as ENCODE, Roadmap Epigenomics, TCGA, and other large- scale genomics projects, which currently discard most TE derived sequences from their data. Such improvement will in turn accelerate research into understanding the impact of TEs'on normal gene regulation and in human diseases.
Transposable elements (TEs) are a special class of DNA sequences which copy themselves and hop to many different locations in the genome. TEs are often referred to as junk DNA or parasitic DNA because they spread through the genome without apparent benefit to the host, and sometimes at the expense of the host. These elements comprise a huge fraction of the DNA in mammalian genomes, including 50% of the human genome. Because of their repetitive nature they are generally discarded in most genomics studies. We recently showed that these elements often carry regulatory sequences that are co-opted by host genomes to perform normal gene regulation. Here we propose to study the extent to which TEs contribute to normal gene regulation throughout the genome and how mis-regulation of TE derived sequences contributes to disease.
|Wang, Yanli; Song, Fan; Zhang, Bo et al. (2018) The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions. Genome Biol 19:151
|Sundaram, Vasavi; Wang, Ting (2018) Transposable Element Mediated Innovation in Gene Regulatory Landscapes of Cells: Re-Visiting the ""Gene-Battery"" Model. Bioessays 40:
|Cheng, Cheng; Deng, Pan-Yue; Ikeuchi, Yoshiho et al. (2018) Characterization of a Mouse Model of Börjeson-Forssman-Lehmann Syndrome. Cell Rep 25:1404-1414.e6
|Zhang, Chengkang; Lee, Hyung Joo; Shrivastava, Anura et al. (2018) Long-Term In Vitro Expansion of Epithelial Stem Cells Enabled by Pharmacological Inhibition of PAK1-ROCK-Myosin II and TGF-? Signaling. Cell Rep 25:598-610.e5
|Jiang, Kaiyu; Wong, Laiping; Chen, Yanmin et al. (2018) Soluble inflammatory mediators induce transcriptional re-organization that is independent of dna methylation changes in cultured human chorionic villous trophoblasts. J Reprod Immunol 128:2-8
|Xing, Xiaoyun; Zhang, Bo; Li, Daofeng et al. (2018) Comprehensive Whole DNA Methylome Analysis by Integrating MeDIP-seq and MRE-seq. Methods Mol Biol 1708:209-246
|Agrawal, A; Chou, Y-L; Carey, C E et al. (2018) Genome-wide association study identifies a novel locus for cannabis dependence. Mol Psychiatry 23:1293-1302
|Dai, Xiaoyu; Lin, Nan; Li, Daofeng et al. (2018) A non-randomized procedure for large-scale heterogeneous multiple discrete testing based on randomized tests. Biometrics :
|Zhu, Liangliang; Yan, Feihu; Wang, Zhen et al. (2018) Genome-wide DNA methylation profiling of primary colorectal laterally spreading tumors identifies disease-specific epimutations on common pathways. Int J Cancer 143:2488-2498
|Zhou, Jia; Sears, Renee L; Xing, Xiaoyun et al. (2017) Tissue-specific DNA methylation is conserved across human, mouse, and rat, and driven by primary sequence conservation. BMC Genomics 18:724
Showing the most recent 10 out of 39 publications