Interspecies regulatory landscapes and elements revealed by novel joint systematic integration of human and mouse blood cell epigenomes

Guanjue Xiang, Xi He, Belinda M. Giardine, Kathryn J. Isaac, Dylan J. Taylor, Rajiv C. McCoy, Camden Jansen, Cheryl A. Keller, Alexander Q. Wixom, April Cockburn, Amber Miller, Qian Qi, Yanghua He, Yichao Li, Jens Lichtenberg, Elisabeth F. Heuston, Stacie M. Anderson, Jing Luan, Marit W. Vermunt, Feng YueMichael E.G. Sauria, Michael C. Schatz, James Taylor, Berthold Göttgens, Jim R. Hughes, Douglas R. Higgs, Mitchell J. Weiss, Yong Cheng, Gerd A. Blobel, David M. Bodine, Yu Zhang, Qunhua Li, Shaun Mahony, Ross C. Hardison*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 fromamultivariate 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, harbor distinctive transcription factor binding motifs that are similar between species. An interspecies comparison of cCREs revealed both conserved and species-specific patterns of epigenetic evolution. Finally, we show that comparisons of the epigenetic landscape between species can reveal elements with similar roles in regulation, even in the absence of genomic sequence alignment.

Original languageEnglish (US)
Pages (from-to)1089-1105
Number of pages17
JournalGenome research
Volume34
Issue number7
DOIs
StatePublished - Jul 2024

Funding

M.C.S., D.M.B., D.R.H., J.R.H., and B.G.; R01DK054937 to G.A.B.; R01GM121613 to Y.Z. and S.M.; R01GM109453 to Q.L.; R35GM133747 to R.C.M.; F31HG012900 to D.J.T.; R01HG011139; National Science Foundation DBI CAREER 2045500 to S.M.; and intramural funds from the National Human Genome Research Institute. We dedicate this paper to the memory of J.T. This work was supported by grants from the National Institutes of Health: R24DK106766 to R.C.H., G.A.B., M.J.W., Y.Z., F.Y., J.T., M.C.S., D.M.B., D.R.H., J.R.H., and B.G.; R01DK054937 to G.A.B.; R01GM121613 to Y.Z. and S.M.; R01GM109453 to Q.L.; R35GM133747 to R.C.M.; F31HG012900 to D.J.T.; R01HG011139; National Science Foundation DBI CAREER 2045500 to S.M.; and intramural funds from the National Human Genome Research Institute. We dedicate this paper to the memory of J.T. Author contributions: G.X., X.H., B.M.G., K.J.I., D.J.T., C.J., A.Q.W., Y.L., Je.L., M.E.G.S., S.M., and R.C.H. performed statistical and computational modeling and analysis; C.A.K., A.Q.W., A.C., A.M., Q.Q., Y.H., E.F.H., S.M.A., Ji.L., and M.W.V. conducted the experiments; G.X., R.C.M., F.Y., M.C.S., J.T., B.G., J.R.H., D.R.H., M.J.W., Y.C., G.A.B., D.M.B., Y.Z., Q.L., S.M., and R.C.H. designed and supervised the experiments and analyses; and G.X., X.H., B.M.G., K.J.I., D.J.T., R.C.M., C.J., Q.L., S.M., and R.C.H. wrote the paper. This work was supported by grants from the National Institutes of Health: R24DK106766 to R.C.H., G.A.B., M.J.W., Y.Z., F.Y., J.T.,

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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