RT Journal Article SR Electronic T1 Cross-species regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes JF bioRxiv FD Cold Spring Harbor Laboratory SP 2023.04.02.535219 DO 10.1101/2023.04.02.535219 A1 Guanjue Xiang A1 Xi He A1 Belinda M. Giardine A1 Kathryn J. Weaver A1 Dylan J. Taylor A1 Rajiv C. McCoy A1 Camden Jansen A1 Cheryl A. Keller A1 Alexander Q. Wixom A1 April Cockburn A1 Amber Miller A1 Qian Qi A1 Yanghua He A1 Yichao Li A1 Jens Lichtenberg A1 Elisabeth F. Heuston A1 Stacie M. Anderson A1 Jing Luan A1 Marit W. Vermunt A1 Feng Yue A1 Michael E.G. Sauria A1 Michael C. Schatz A1 James Taylor A1 Berthold Göttgens A1 Jim R. Hughes A1 Douglas R. Higgs A1 Mitchell J. Weiss A1 Yong Cheng A1 Gerd A. Blobel A1 David Bodine A1 Yu Zhang A1 Qunhua Li A1 Shaun Mahony A1 Ross C. Hardison YR 2023 UL http://biorxiv.org/content/early/2023/04/04/2023.04.02.535219.abstract AB Knowledge of locations and activities of cis-regulatory elements (CREs) is needed to decipher basic mechanisms of gene regulation and to understand the impact of genetic variants on complex traits. Previous studies identified candidate CREs (cCREs) using epigenetic features in one species, making comparisons difficult across species. In contrast, we conducted a cross-species study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable across species. This study used integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The contribution of each epigenetic state in cCREs to gene regulation was estimated from a multivariate regression against gene expression across cell types. We used these values to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which are useful for visualizing and categorizing dynamic changes in cCREs. Groups of cCREs displaying similar patterns of regulatory activity in human and mouse cell types, obtained by joint clustering on esRP scores, harbored distinctive transcription factor binding motifs that were similar across species. Genetic variants associated with blood cell phenotypes were highly and specifically enriched in the catalog of human VISION cCREs, supporting its utility for understanding impacts of noncoding genetic variants on blood cell-related traits. A cross-species comparison of cCREs, based on the joint modeling, revealed both conserved and lineage-specific patterns of epigenetic evolution, even in the absence of genomic sequence alignment. We provide these resources through tools and browsers at http://usevision.org.Competing Interest StatementThe authors have declared no competing interest.