Our long-term goal is to understand the mechanisms by which sequence variations in enhancers affect gene expression. Genome-wide association study (GWAS) and expression quantitative trait loci (eQTL) mapping have revealed thousands of sequence variants that are associated with common diseases and gene expression variations. A large portion of the associated variants is located far away from genes, making them difficult to interpret. Given its abundance and essential role in gene regulation, sequence variants in transcriptional enhancers could be the cause of many phenotypic variations. Currently, identifying such variants remains a challenge because of several hurdles: i) rudimentary annotation of tissue-specific enhancers; ii) lack of strategies to precisely pinpoint the identity and location of transcription factor binding sites (TFBSs) within an enhancer; and iii lack of strategies to assign enhancer targets. By addressing these hurdles, the objective of this project is to design and test a computational framework that enables systematic and rapid screen of enhancer sequence variants that cause complex diseases. As an ultimate test of our approach, we will apply our computational strategy to screen and characterize enhancer variants that are associated with a common autoimmune disease, Type 1 Diabetes. To make the methods developed in this project useful to a much broader community of users, we will develop an open-source software suite and a database dedicated to the analysis and curation of regulatory mutations in enhancers. It is anticipated that the outcomes of this project will have an important positive impact because it promises to significantly accelerate the discovery and systematic documentation of causal genetic variants in the noncoding portion of the human genome.
Thousands of genetic variants have been associated with human diseases but very few successful findings of actual etiologic variants have been reported. The need for computational and high throughput methods is essential to accelerate the discovery of disease-causing variants.
|Tober, Joanna; Maijenburg, Marijke M W; Li, Yan et al. (2018) Maturation of hematopoietic stem cells from prehematopoietic stem cells is accompanied by up-regulation of PD-L1. J Exp Med 215:645-659|
|Gao, Long; Uzun, Yasin; Gao, Peng et al. (2018) Identifying noncoding risk variants using disease-relevant gene regulatory networks. Nat Commun 9:702|
|Li, Yan; Gao, Long; Hadland, Brandon et al. (2017) CD27 marks murine embryonic hematopoietic stem cells and type II prehematopoietic stem cells. Blood 130:372-376|
|Li, Fengyin; He, Bing; Ma, Xiaoke et al. (2017) Prostaglandin E1 and Its Analog Misoprostol Inhibit Human CML Stem Cell Self-Renewal via EP4 Receptor Activation and Repression of AP-1. Cell Stem Cell 21:359-373.e5|
|Yu, Wenbao; He, Bing; Tan, Kai (2017) Identifying topologically associating domains and subdomains by Gaussian Mixture model And Proportion test. Nat Commun 8:535|
|He, Bing; Xing, Shaojun; Chen, Changya et al. (2016) CD8+ T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections. Immunity 45:1341-1354|
|Gao, Tianshun; He, Bing; Liu, Sheng et al. (2016) EnhancerAtlas: a resource for enhancer annotation and analysis in 105 human cell/tissue types. Bioinformatics 32:3543-3551|
|He, Bing; Tan, Kai (2016) Understanding transcriptional regulatory networks using computational models. Curr Opin Genet Dev 37:101-108|
|Holmfeldt, Per; Ganuza, Miguel; Marathe, Himangi et al. (2016) Functional screen identifies regulators of murine hematopoietic stem cell repopulation. J Exp Med 213:433-49|
|Huang, Jianfei; Wang, Kai; Wei, Peng et al. (2016) FLAGS: A Flexible and Adaptive Association Test for Gene Sets Using Summary Statistics. Genetics 202:919-29|
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