VISION: ValIdated Systematic IntegratiON of hematopoietic epigenomes Technological advances enabling the production of large numbers of rich, genome-wide, sequence-based datasets have transformed biology. However, the volume of data is overwhelming for most investigators. Also, we do not know the mechanisms by which the vast majority of epigenetic features regulate normal differentiation or lead to aberrant function in disease. We have formed an interdisciplinary, collaborative team of investigators to address the problem of how to effectively utilize the enormous amount of epigenetic data both for basic research and precision medicine. At this point, acquisition of data is no longer the major barrier to understanding mechanisms of gene regulation during normal and pathological tissue development. The chief challenges are how to: (i) integrate epigenetic data in terms that are accessible and understandable to a broad community of researchers, (ii) build validated quantitative models explaining how the dynamics of gene expression relates to epigenetic features, and (iii) translate information effectively from mouse models to potential applications in human health. These needs are addressed by the proposed ValIdated Systematic IntegratiON (VISION) of epigenetic data to analyze mouse and human hematopoiesis, a tractable system with clear clinical significance and importance to NIDDK. By pursuing the following Specific Aims, the interdisciplinary collaboration will deliver comprehensive catalogs of cis regulatory modules (CRMs), extensive chromatin interaction maps and deduced regulatory domains, validated quantitative models for gene regulation, and a guide for investigators to translate insights from mouse models to human clinical studies. These deliverables will be provided to the community in readily accessible, web-based platforms including customized genome browsers, databases with facile query interfaces, and data-driven on-line tools. Specifically, the proposed work in Aim 1 will build comprehensive, integrative catalogs of hematopoietic CRMs and transcriptomes by compiling and determining informative epigenetic features and transcript levels in hematopoietic stem and progenitor cells and in mature cells. CRMs will be predicted using the novel IDEAS (Integrative and Discriminative Epigenome Annotation System) method. Work proposed in Aim 2 will build and validate quantitative models for gene regulation informed by chromatin interaction maps and epigenetic data. Compiling and determining chromosome interaction frequencies will predict likely target genes for CRMs. Gene regulatory models will be built that predict the contributions of CRMs and specific proteins to regulated expression; these models will be validated by extensive testing using genome-editing in ten reference loci. Finally, work in Aim 3 will produce a guide for investigators to translate insights from mouse models to human clinical studies. This effort will include categorizing orthologous mouse and human genes by conservation versus divergence of expression patterns, assigning CRMs to informative categories of epigenomic evolution, and testing the interspecies functional maps experimentally by genome-editing.
VISION: ValIdated Systematic IntegratiON of hematopoietic epigenomes Blood cell formation is vitally important to human health because we must continually replace old and damaged cells, and because many diseases result from mis-regulation of gene expression during blood formation. Global measurements of proteins bound to DNA and their modifications help us find the genetic differences most likely to account for the aberrant gene expression at the heart of some diseases. Our formal modeling and experimental tests will open windows of insight to improve application of basic research in gene regulation to clinical studies.
|Lescroart, Fabienne; Wang, Xiaonan; Lin, Xionghui et al. (2018) Defining the earliest step of cardiovascular lineage segregation by single-cell RNA-seq. Science 359:1177-1181|
|Heuston, Elisabeth F; Keller, Cheryl A; Lichtenberg, Jens et al. (2018) Establishment of regulatory elements during erythro-megakaryopoiesis identifies hematopoietic lineage-commitment points. Epigenetics Chromatin 11:22|
|Philipsen, Sjaak; Hardison, Ross C (2018) Evolution of hemoglobin loci and their regulatory elements. Blood Cells Mol Dis 70:2-12|
|Bartman, Caroline R; Hamagami, Nicole; Keller, Cheryl A et al. (2018) Transcriptional Burst Initiation and Polymerase Pause Release Are Key Control Points of Transcriptional Regulation. Mol Cell :|
|Zhang, Yan; An, Lin; Xu, Jie et al. (2018) Enhancing Hi-C data resolution with deep convolutional neural network HiCPlus. Nat Commun 9:750|
|Ibarra-Soria, Ximena; Jawaid, Wajid; Pijuan-Sala, Blanca et al. (2018) Defining murine organogenesis at single-cell resolution reveals a role for the leukotriene pathway in regulating blood progenitor formation. Nat Cell Biol 20:127-134|
|Behera, Vivek; Evans, Perry; Face, Carolyne J et al. (2018) Exploiting genetic variation to uncover rules of transcription factor binding and chromatin accessibility. Nat Commun 9:782|
|Dixon, Jesse R; Xu, Jie; Dileep, Vishnu et al. (2018) Integrative detection and analysis of structural variation in cancer genomes. Nat Genet 50:1388-1398|
|Liao, Chang; Hardison, Ross C; Kennett, Mary J et al. (2018) Selenoproteins regulate stress erythroid progenitors and spleen microenvironment during stress erythropoiesis. Blood 131:2568-2580|
|Laurenti, Elisa; Göttgens, Berthold (2018) From haematopoietic stem cells to complex differentiation landscapes. Nature 553:418-426|
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