At the Center for Epigenomics, every project is a collaboration. Its research team is currently working with numerous collaborators across the San Diego mesa, and leverages it's unique capabilities to drive projects forward. The Center is a shining example of what has always made UC San Diego unique: a deep-rooted culture of working across disciplines to answer complex questions. The following are highlights of our collaborative research.
Generating a spatially resolved single cell epigenome atlas of the mouse brain as part of the BRAIN initiative
Collaborators: Dr. Joseph Ecker, Dr. Edward Callaway, Dr. Margarita Behrens, Dr, Eran Mukamel, Salk
The mammalian brain comprises thousands of distinct cell types and is highly spatially organized to properly execute its diverse functions. Cell type-specific and spatially resolved gene expression patterns are largely driven by cis-regulatory regions in the genome including promoters and distal acting enhancers. Thus, identifying and characterizing these elements by single cell DNA methylome and chromatin accessibility analysis is crucial to our understanding of gene regulation in the brain. As part of this collaboration, we are utilizing single nucleus ATAC-seq to profile chromatin accessibility in more than a million single cells from > 100 regions of the mouse brain. This rich resource of chromatin accessibility in the mouse brain at single cell resolution will build a basis for understanding the gene regulatory architecture of the mammalian brain and its role in tissue function and disease. Funding: 1U19MH114831-01 (CoI: Bing Ren)
Generating a cell atlas for type I diabetes as part of the Human Islet Research Network (HIRN)
Collaborators: Dr. Maike Sander, Dr. Kyle Gaulton, UC San Diego
In type 1 diabetes (T1D) the interplay between immune cells, endothelial cells, and beta cells in the islet niche leads to beta cell dysfunction and/or destruction; however, there is limited knowledge of the molecular blueprint that initiates and drives immune-mediated beta cell destruction. This collaboration between the Center for Epigenomics and Drs. Sander and Gaulton fills this knowledge gap by applying novel single cell technologies to characterize the transcriptional and epigenetic profiles of individual disease-relevant cells in the pancreas of nondiabetic and T1D donors. This project aims to provide novel insight into the pathogenic processes of cells in the pancreatic microenvironment that lead to beta cells loss in T1D. Funding 1U01DK120429-01 (CoI's: David Gorkin, Sebastian Preissl)
A single cell atlas of gene regulatory elements in the human heart to decode cardiovascular diseases
Collaborators: Dr. Neil Chi, Dr. Kyle Gaulton, UC San Diego
Heart disease is the leading cause of death in the western world and heart failure is the leading cause of heart transplantation in the United States. However, there is limited knowledge of the molecular mechanism and gene regulatory networks underlying cardiac disease and a lack of cell-type specific annotation of risk variants associated with cardiovascular diseases. To fill in this gap, this project employs single nucleus ATAC-seq to elucidate cardiac cell type-specific gene regulatory elements in more than 200,000 nuclei isolated from adult human hearts. Thus, this dataset builds the foundation for a cardiac atlas of gene regulatory networks in the human heart and cardiac disease.
Interrogating molecular mechanisms of lung disease at single-cell resolution
Collaborators: Dr. Xin Sun, Dr. Kyle Gaulton, UC San Diego
The human lung is composed of a ramifying network of airways and blood vessels that connect millions of alveoli to the aerosol environment. Weaved into this vast organ are exquisite regional differences in the form of cellular niches best defined at single-cell resolution. Emerging evidence shows that seamless collaboration between these specialized niches is fundamental for lung function and these niches are often sites of pathogenesis. We are generating single cell maps of these niches using single nuclei ATAC-seq and RNA-seq to unravel the molecular mechanisms underlying niche diversity and interplay.
Development of high-throughput ATAC-seq (ht-ATAC-seq)
With Beckman Coulter
The Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) is a powerful tool for studying regulatory DNA sequences that direct gene expression in response to specific developmental and environmental cues. However, the current throughput and cost of ATAC-seq are barriers to its use in individualized medicine and high throughput screening. In partnership with Beckman Coulter, researchers at the Center for Epigenomics are employing liquid handling robotics to increase the throughput and drive down the cost of ATAC-seq. We are taking advantage of this improved capacity to screen potential chemotherapeutics, profile patient biosamples, and support a variety of collaborative research efforts.
Publications from Center Collaboration
Pijuan-Sala, B, Wilson, NK, Xia, J, Hou, X, Hannah, RL, Kinston, S, Calero-Nieto, FJ, Poirion, O, Preissl, S, Liu, F, Göttgens, B. Single-cell chromatin accessibility maps reveal the regulatory programs driving early mouse organogenesis. Nature Cell Biology. 2020 Apr;22(4):487-497. doi: 10.1038/s41556-020-0489-9. PMID: 32231307.
Gorkin, DU, Qiu, Y, Hu, M, Fletez-Brant, K, Liu, T, Schmitt, AD, Noor, A, Chiou, J, Gaulton, KJ, Sebat, J, Li, Y, Hansen, KD, Ren, B. Common DNA sequence variation influences 3-dimensional architecture of the human genome. Genome Biology. 2019 Nov 28;20(1):255. doi: 10.1186/s13059-019-1855-4. PMID: 31779666.
Jameson, NM, Ma, J, Benitez, J, Izurieta, A, Han, JY, Mendez, R, Parisian, A, Furnari, F. Intron 1-mediated regulation of EGFR expression in EGFR-dependent malignancies is mediated by AP-1 and BET proteins. Molecular Cancer Research. 2019 Nov;17 (11):2208-2220. doi: 10.1158/1541-7786.MCR-19-0747. PMID: 31444232
Chung, CY, Ma, Z, Dravis, C, Preissl, S, Poirion, O, Luna, G, Hou, X, Giraddi, RR, Ren, B, Wahl, GM. Single-cell chromatin accessibility analysis of mammary gland development reveals cell state transcriptional regulators and cellular lineage relationships. Cell Reporter. 2019 Oct 8;29(2):495-510.e6. doi: 10.1016/j. PMID:31597106
Zhang, Y, Li, T, Preissl, S, Grinstein, J, Farah, EN, Destici, E, Lee, AY, Chee, S, Qiu, Y, Ma, K, Ye, Z, Hu, R, Zhu, Q, Huang, H, Fang, R, Yu, L, Izpisua Belmonte, JC, Wu, J, Evans, SM, Chi, NC, Ren, B. Transcriptionally active HERV-H retrotransposons demarcate topologically associating domains in human pluripotent stem cells. Nature Genetics. 2019 Sep;51(9):1380-1388. doi: 10.1038/s41588-019-0479-7. PMID: 31427791.
Greenwald, WW, Chiou, J, Yan, J, Qiu, Y, Dai, N, Wang, A, Nariai, N, Aylward, A, Han, JY, Kadakia, N, Regue, L, Okino, ML, Drees, F, Kramer, D, Vinckier, N, Minichiello, L, Gorkin, DU, Avruch, J, Frazer, KA, Sander, M, Ren B, Gaulton, KJ. Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk. Nature Communications. 2019 May 7; 10(1):2078. doi: 10.1038/s41467-019-09975-4. PMID: 31064983.
Xie, Q, Wu, TP, Gimple, RC, Li, Z, Prager, BC, Wu, Q, Yu, Y, Wang, P, Wang Y, Gorkin, DU, Zhang, C, Dowiak, AV, Lin, K, Zeng, C, Sui, Y, Kim, LJY, Miller, TE, Jiang, L, Lee, CH, Huang, Z, Fang, X, Zhai, K, Mack, SC, Sander, M, Bao, S, Kerstetter-Fogle, AE, Sloan, AE, Xiao, AZ, Rich, JN. N6-methyladenine DNA Modification in Glioblastoma. Cell. 2018 Nov 15;175(5):1228-1243.e20. doi: 10.1016/j.cell.2018.10.006. PMID: 30392959.
Li, R, Bernau, K, Sandbo, N, Gu, J, Preissl, S, Sun, X. Pdgfra marks a cellular lineage with distinct contributions to myofibroblasts in lung maturation and injury response. Elife. 2018 Sep 4;7:e36865. doi: 10.7554/eLife.36865. PMID: 30178747.
Preissl, S, Fang, R, Huang, H, Zhao, Y, Raviram, R, Gorkin, DU, Zhang Y, Sos ,BC, Afzal, V, Dickel, DE, Kuan, S, Visel, A, Pennacchio, LA, Zhang, K, Ren, B. Single-nucleus analysis of accessible chromatin in developing mouse forebrain reveals cell-type-specific transcriptional regulation. Nature Neuroscience. 2018 Mar;21(3):432-439. doi: 10.1038/s41593-018-0079-3. PMID: 29434377.
Li, Y, Preissl, S, Hou, X, Zhang, Z, Zhang, K, Fang, R, Qiu, Y, Poirion, O, Li, B, Yan, Y, Liu, H, Wang, X, Han, JY, Lucero, J, Kuan, S, Gorkin, D, Nunn, M, Mukamel, EA, Behrens, MM, Ecker, JR, Ren, B. An Atlas of Gene Regulatory Elements in Adult Mouse Cerebrum. bioRxiv. doi: https://doi.org/10.1101/2020.05.10.087585.
Wang, A, Chiou, J, Poirion, OB, Buchanan, J, Valdez, MJ, Verheyden, JM, Hou, X, Guo, M, Newsome, JM, Kudtarkar, P, Faddah, DA, Zhang, K, Young, RE, Barr, J, Misra, R, Huyck, H, Rogers, L, Poole, C, Whitsett, JA, Pryhuber, G, Xu, Y, Gaulton, KJ, Preissl, S, Xin Sun, NHLBI LungMap Consortium. Single nucleus multiomic profiling reveals age-dynamic regulation of host genes associated with SARS-CoV-2 infection. bioRxiv. doi: https://doi.org/10.1101/2020.04.12.037580.
Yao, Z, Liu, H, Xie, F, Fischer, S, Booeshaghi, AS, Adkins, RS, Aldridge, AI, Ament, SA, Pinto-Duarte, A, Bartlett, A, Behrens, MM, Van den Berge, K, Bertagnolli, D, Biancalani, T, Bravo, HC, Casper, T, Colantuoni, C, Creasy, H, Crichton, K, Crow, M, Dee, N, Dougherty, EL, Doyle, WI, Dudoit, S, Fang, R, Felix, V, Fong, O, Giglio, M, Goldy, J, Hawrylycz, M, Roux de Bézieux, H, Herb, BR, Hertzano, R, Hou, X, Hu, Q, Crabtree, J, Kancherla, J, Kroll, M, Lathia, K, Li, YE, Lucero, JD, Luo, C, Mahurkar, A, McMillen, D, Nadaf, N, Nery, JR, Niu, SY, Orvis, J, Osteen, JK, Pham, T, Poirion, O, Preissl, S, Purdom, E, Rimorin, C, Risso, D, Rivkin, AC, Smith, K, Street, K, Sulc, J, Nguyen, TN, Tieu, M, Torkelson, A, Tung, H, Vaishnav, ED, Svensson, V, Vanderburg, CR, Ntranos, V, van Velthoven, C, Wang, X, White, OR, Huang, ZJ, Kharchenko, PV, Pachter, L, Ngai, J, Regev, A, Tasic, B, Welch, JD, Gillis, J, Macosko, EZ, Ren, B, Ecker, JR, Zeng, H, Mukame, EA. An integrated transcriptomic and epigenomic atlas of mouse primary motor cortex cell types. bioRxiv. doi: https://doi.org/10.1101/2020.02.29.970558.
Gao, C, Preissl, S, Luo, C, Castanon, R, Sandoval, J, Rivkin, A, Nery, JR, Behrens, MM, Ecker, JR, Ren, B, Welch, JD. Iterative refinement of cellular identity from single-cell data using online learning. bioRxiv. doi: https://doi.org/10.1101/2020.01.16.909861.
Luo, C, Liu, H, Xie, F, Armand, EJ, Siletti, K, Bakken, TE, Fang, R, Doyle, WI, Hodge, RD, Hu, L, Wang, BA, Zhang, Z, Preissl, S, Lee, DS, Zhou, J, Niu, SY, Castanon, R, Bartlett, A, Rivkin, A, Wang, X, Lucero, J, Nery, JR, Davis, DA, Mash, DC, Dixon, JR, Linnarsson, S, Lein, E, Behrens, MM, Ren, B, Mukamel, EA, Ecker, JR. Single nucleus multi-omics links human cortical cell regulatory genome diversity to disease risk variants. bioRxiv. doi: https://doi.org/10.1101/2019.12.11.873398.
Fang, R, Preissl, S, Hou, X, Lucero, J, Wang, X, Motamedi, A, Shiau, AK, Mukamel, EA, Zhang, Y, Behrens, MM, Ecker, J, Ren, B. Fast and Accurate Clustering of Single Cell Epigenomes Reveals Cis-Regulatory Elements in Rare Cell Types. bioRxiv. doi: https://doi.org/10.1101/615179.
Chiou, J, Zeng, C, Cheng, Z, Han, JY, Schlichting, M, Huang, S, Wang, J, Sui, Y, Deogaygay, A, Okino, ML, Qiu, Y, Sun, Y, Kudtarkar, P, Fang, R, Preissl, S, Sander, M, Gorkin, DU, Gaulton, KJ. Single cell chromatin accessibility reveals pancreatic islet cell type- and state-specific regulatory programs of diabetes risk. bioRxiv. doi: https://doi.org/10.1101/693671.
Gorkin, DU, Barozzi, I, Zhang, Y, Lee, AY, Li, B, Zhao,Y, Wildberg, A, Ding, B, Zhang, B, Wang, M, Strattan, JS, Davidson, JM, Qiu, Y, Afzal, V, Akiyama, JA, Plajzer-Frick, I, Pickle, CS, Kato, M, Garvin, TH, Pham, QT, Harrington, AN, Mannion, BJ, Lee, EA, Fukuda-Yuzawa, Y, He, Y, Preissl, S, Chee, S, Williams, BA, Trout, D, Amrhein, H, Yang, H, Cherry, JM, Shen, Y, Ecker, JR, Wang, W, Dickel, DE, Visel, A, Pennacchio, LA, Ren, B. Systematic mapping of chromatin state landscapes during mouse development. bioRxiv. doi: https://doi.org/10.1101/166652.