An expanded registry of candidate cis-regulatory elements

Jill E Moore¹, Henry E Pratt², Kaili Fan², Nishigandha Phalke², Jonathan Fisher², Shaimae I Elhajjajy², Gregory Andrews², Mingshi Gao², Nicole Shedd², Yu Fu², Matthew C Lacadie², Jair Meza², Mansi Khandpekar², Mohit Ganna², Eva Choudhury², Ross Swofford², Huong Phan², Christian C Ramirez², Maxwell Campbell², Mary Likhite², Nina P Farrell³, Annika K Weimer⁴, Anusri Pampari⁵, Vivekanandan Ramalingam⁴, Fairlie Reese⁶, Beatrice Borsari^{7

8}, Xuezhu Yu^{7

8}, Eve Wattenberg^{7

8}, Marina Ruiz-Romero⁹, Milad Razavi-Mohseni¹⁰, Jinrui Xu¹¹, Timur Galeev^{7

8}, Andres Colubri^{2

3}, Michael A Beer¹⁰, Roderic Guigó^{9

12}, Mark B Gerstein^{7

8

13

14

15

16}, Jesse M Engreitz^{4

17

18

19}, Mats Ljungman²⁰, Timothy E Reddy^{21

22

23}, Michael P Snyder⁴, Charles B Epstein³, Elizabeth Gaskell³, Bradley E Bernstein³, Diane E Dickel²⁴, Axel Visel^{24

25

26}, Len A Pennacchio²⁴, Ali Mortazavi^{6

27}, Anshul Kundaje^{4

5}, Zhiping Weng²⁸

Affiliations

¹ Department of Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA. Jill.Moore@umassmed.edu.
² Department of Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Genetics, Stanford University, Stanford, CA, USA.
⁵ Department of Computer Science, Stanford University, Stanford, CA, USA.
⁶ Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA.
⁷ Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
⁸ Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
⁹ Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
¹⁰ Department of Biomedical Engineering and McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹¹ Department of Biology and Center for Applied Data Science and Analytics, Howard University, Washington, DC, USA.
¹² Universitat Pompeu Fabra (UPF), Barcelona, Spain.
¹³ Program in Computational Biology and Biomedical Informatics, Yale University, New Haven, CT, USA.
¹⁴ Department of Computer Science, Yale University, New Haven, CT, USA.
¹⁵ Department of Statistics and Data Science, Yale University, New Haven, CT, USA.
¹⁶ Department of Biomedical Informatics and Data Science, Yale University, New Haven, CT, USA.
¹⁷ Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA, USA.
¹⁸ Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute, Cambridge, MA, USA.
¹⁹ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
²⁰ Departments of Radiation Oncology and Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA.
²¹ Duke Center for Statistical Genetics and Genomics, Duke University, Durham, NC, USA.
²² Division of Integrative Genomics, Department of Biostatistics Bioinformatics, Duke University Medical School, Durham, NC, USA.
²³ Center for Genomic and Computational Biology, Duke University Medical School, Durham, NC, USA.
²⁴ Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
²⁵ US Department of Energy Joint Genome Institute, Berkeley, CA, USA.
²⁶ School of Natural Sciences, University of California, Merced, Merced, CA, USA.
²⁷ Center for Complex Biological Systems, University of California Irvine, Irvine, CA, USA.
²⁸ Department of Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA. zhiping.weng@umassmed.edu.

PMID: 41501460
DOI: 10.1038/s41586-025-09909-9

An expanded registry of candidate cis-regulatory elements

Jill E Moore et al. Nature. 2026.

. 2026 Jan 7.

doi: 10.1038/s41586-025-09909-9. Online ahead of print.

Authors

Affiliations

¹ Department of Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA. Jill.Moore@umassmed.edu.
² Department of Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Department of Genetics, Stanford University, Stanford, CA, USA.
⁵ Department of Computer Science, Stanford University, Stanford, CA, USA.
⁶ Developmental and Cell Biology, University of California Irvine, Irvine, CA, USA.
⁷ Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
⁸ Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
⁹ Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.
¹⁰ Department of Biomedical Engineering and McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹¹ Department of Biology and Center for Applied Data Science and Analytics, Howard University, Washington, DC, USA.
¹² Universitat Pompeu Fabra (UPF), Barcelona, Spain.
¹³ Program in Computational Biology and Biomedical Informatics, Yale University, New Haven, CT, USA.
¹⁴ Department of Computer Science, Yale University, New Haven, CT, USA.
¹⁵ Department of Statistics and Data Science, Yale University, New Haven, CT, USA.
¹⁶ Department of Biomedical Informatics and Data Science, Yale University, New Haven, CT, USA.
¹⁷ Basic Sciences and Engineering Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford, CA, USA.
¹⁸ Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute, Cambridge, MA, USA.
¹⁹ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.
²⁰ Departments of Radiation Oncology and Environmental Health Sciences, University of Michigan, Ann Arbor, MI, USA.
²¹ Duke Center for Statistical Genetics and Genomics, Duke University, Durham, NC, USA.
²² Division of Integrative Genomics, Department of Biostatistics Bioinformatics, Duke University Medical School, Durham, NC, USA.
²³ Center for Genomic and Computational Biology, Duke University Medical School, Durham, NC, USA.
²⁴ Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
²⁵ US Department of Energy Joint Genome Institute, Berkeley, CA, USA.
²⁶ School of Natural Sciences, University of California, Merced, Merced, CA, USA.
²⁷ Center for Complex Biological Systems, University of California Irvine, Irvine, CA, USA.
²⁸ Department of Genomics and Computational Biology, UMass Chan Medical School, Worcester, MA, USA. zhiping.weng@umassmed.edu.

PMID: 41501460
DOI: 10.1038/s41586-025-09909-9

Abstract

Mammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression¹. Previously, the ENCODE consortium mapped biochemical signals across hundreds of cell types and tissues and integrated these data to develop a registry containing 0.9 million human and 300,000 mouse candidate cis-regulatory elements (cCREs) annotated with potential functions². Here we have expanded the registry to include 2.37 million human and 967,000 mouse cCREs, leveraging new ENCODE datasets and enhanced computational methods. This expanded registry covers hundreds of unique cell and tissue types, providing a comprehensive understanding of gene regulation. Functional characterization data from assays such as STARR-seq³, massively parallel reporter assay⁴, CRISPR perturbation^5,6 and transgenic mouse assays⁷ have profiled more than 90% of human cCREs, revealing complex regulatory functions. We identified thousands of novel silencer cCREs and demonstrated their dual enhancer and silencer roles in different cellular contexts. Integrating the registry with other ENCODE annotations facilitates genetic variation interpretation and trait-associated gene identification, exemplified by the identification of KLF1 as a novel causal gene for red blood cell traits. This expanded registry is a valuable resource for studying the regulatory genome and its impact on health and disease.

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Conflict of interest statement

Competing interests: J.M.E. is an inventor on patents and patent applications related to CRISPR screening technologies, has received materials from 10× Genomics unrelated to this study, and has received speaking honoraria from GSK, Amgen, and Genentech. B.E.B. discloses financial interests in HiFiBio, Arsenal Biosciences, Chroma Medicine and Cell Signaling Technologies. M.P.S. is a co-founder and on the advisory boards of Personalis, Qbio, January AI, SensOmics, Filtricine, Protos, Mirvie, Onza, Marble Therapeutics, Iollo and NextThought AI. He is also on the advisory boards of Jupiter, Applied Cognition, Neuvivo, Mitrix, and Enovone. A.K. is a consulting fellow with Illumina; a member of the scientific advisory boards of OpenTargets (GSK), PatchBio and SerImmune; and a co-founder of RavelBio. Z.W. is a co-founder of Rgenta Therapeutics and serves on its scientific advisory board. The other authors declare no competing interests.

Update of

An Expanded Registry of Candidate cis-Regulatory Elements for Studying Transcriptional Regulation.
Moore JE, Pratt HE, Fan K, Phalke N, Fisher J, Elhajjajy SI, Andrews G, Gao M, Shedd N, Fu Y, Lacadie MC, Meza J, Ganna M, Choudhury E, Swofford R, Farrell NP, Pampari A, Ramalingam V, Reese F, Borsari B, Yu M, Wattenberg E, Ruiz-Romero M, Razavi-Mohseni M, Xu J, Galeev T, Beer MA, Guigó R, Gerstein M, Engreitz J, Ljungman M, Reddy TE, Snyder MP, Epstein CB, Gaskell E, Bernstein BE, Dickel DE, Visel A, Pennacchio LA, Mortazavi A, Kundaje A, Weng Z. Moore JE, et al. bioRxiv [Preprint]. 2024 Dec 26:2024.12.26.629296. doi: 10.1101/2024.12.26.629296. bioRxiv. 2024. Update in: Nature. 2026 Jan 7. doi: 10.1038/s41586-025-09909-9. PMID: 39763870 Free PMC article. Updated. Preprint.

References

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An expanded registry of candidate cis-regulatory elements

Affiliations

An expanded registry of candidate cis-regulatory elements

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

References

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