Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes
- Guanjue Xiang1,
- Xi He2,
- Belinda M. Giardine3,
- Kathryn J. Isaac4,
- Dylan J. Taylor4,
- Rajiv C. McCoy4,
- Camden Jansen3,
- Cheryl A. Keller3,
- Alexander Q. Wixom3,
- April Cockburn3,
- Amber Miller3,
- Qian Qi5,
- Yanghua He6,
- Yichao Li5,
- Jens Lichtenberg7,
- Elisabeth F. Heuston7,
- Stacie M. Anderson7,
- Jing Luan8,
- Marit W. Vermunt8,
- Feng Yue9,
- Michael E.G. Sauria4,
- Michael C. Schatz4,
- James Taylor4,
- Berthold Göttgens10,
- Jim R. Hughes11,
- Douglas R. Higgs11,
- Mitchell J. Weiss5,
- Yong Cheng5,
- Gerd A. Blobel8,
- David M. Bodine7,
- Yu Zhang3,
- Qunhua Li12,
- Shaun Mahony12 and
- Ross C. Hardison12,13
- 1 Huck Institutes of the Life Sciences, The Pennsylvania State University, Dana-Farber Cancer Institute, Harvard T.H. Chan School of Public Health;
- 2 Huck Institutes of the Life Sciences, The Pennsylvania State University;
- 3 The Pennsylvania State University;
- 4 Johns Hopkins University;
- 5 St. Jude Children's Research Hospital;
- 6 St. Jude Children's Research Hospital, University of Hawai`i at Manoa;
- 7 National Human Genome Research Institute;
- 8 Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania;
- 9 Northwestern University;
- 10 Welcome and MRC Cambridge Stem Cell Institute, University of Cambridge;
- 11 MRC Weatherall Institute of Molecular Medicine, Oxford University;
- 12 Genome Sciences Institute, Huck Institutes of the Life Sciences, The Pennsylvania State University
Abstract
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 between species. In contrast, we conducted an interspecies study defining epigenetic states and identifying cCREs in blood cell types to generate regulatory maps that are comparable between species, using integrative modeling of eight epigenetic features jointly in human and mouse in our Validated Systematic Integration (VISION) Project. The resulting catalogs of cCREs are useful resources for further studies of gene regulation in blood cells, indicated by high overlap with known functional elements and strong enrichment for human genetic variants associated with blood cell phenotypes. The contribution of each epigenetic state in cCREs to gene regulation, inferred from a multivariate regression, was used to estimate epigenetic state Regulatory Potential (esRP) scores for each cCRE in each cell type, which were used to categorize 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 between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we showed that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.
- Received April 3, 2023.
- Accepted June 24, 2024.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International license), as described at http://creativecommons.org/licenses/by-nc/4.0/.
