DOE OSTI · 3022288
An expanded registry of candidate cis -regulatory elements
Abstract
Mammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression. 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 functions. 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-seq, massively parallel reporter assay, CRISPR perturbation and transgenic mouse assays 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.
Keep this discovery
Explore connections, maps & timelines
Moore, Jill E. [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School] (ORCID:0000000230230806), Pratt, Henry E. [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Fan, Kaili [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School] (ORCID:0000000287237902), Phalke, Nishigandha [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Fisher, Jonathan [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Elhajjajy, Shaimae I. [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Andrews, Gregory [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Gao, Mingshi [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School] (ORCID:000000027524892X), Shedd, Nicole [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Fu, Yu [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Lacadie, Matthew C. [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Meza, Jair [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Khandpekar, Mansi [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Ganna, Mohit [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Choudhury, Eva [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Swofford, Ross [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School] (ORCID:0000000336768479), Phan, Huong [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School] (ORCID:0009000623393806), Ramirez, Christian C. [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Campbell, Maxwell [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School] (ORCID:0009000163520463), Likhite, Mary [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School], Farrell, Nina P. [Broad Institute, Cambridge, MA (United States)], Weimer, Annika K. [Stanford Univ., CA (United States)] (ORCID:0000000199448769), Pampari, Anusri [Stanford Univ., CA (United States)], Ramalingam, Vivekanandan [Stanford Univ., CA (United States)] (ORCID:0000000236318913), Reese, Fairlie [Univ. of California, Irvine, CA (United States)], Borsari, Beatrice [Yale Univ., New Haven, CT (United States)] (ORCID:0000000343573557), Yu, Xuezhu [Yale Univ., New Haven, CT (United States)], Wattenberg, Eve [Yale Univ., New Haven, CT (United States)], Ruiz-Romero, Marina [Barcelona Institute of Science and Technology (BIST) (Spain)] (ORCID:0000000283821052), Razavi-Mohseni, Milad [Johns Hopkins Univ., Baltimore, MD (United States)], Xu, Jinrui [Howard Univ., Washington, DC (United States)], Galeev, Timur [Yale Univ., New Haven, CT (United States)], Colubri, Andres [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School; Broad Institute, Cambridge, MA (United States)], Beer, Michael A. [Johns Hopkins Univ., Baltimore, MD (United States)] (ORCID:0000000199553809), Guigó, Roderic [Barcelona Institute of Science and Technology (BIST) (Spain); Univ. Pompeu Fabra (UPF), Barcelona (Spain)] (ORCID:0000000257384477), Gerstein, Mark B. [Yale Univ., New Haven, CT (United States)] (ORCID:0000000297463719), Engreitz, Jesse M. [Stanford Univ., CA (United States); Lucile Packard Children’s Hospital, Stanford, CA (United States); Broad Institute, Cambridge, MA (United States)] (ORCID:0000000257541719), Ljungman, Mats [Univ. of Michigan, Ann Arbor, MI (United States)] (ORCID:0000000315536695), Reddy, Timothy E. [Duke Univ., Durham, NC (United States)] (ORCID:000000027629061X), Snyder, Michael P. [Stanford Univ., CA (United States)] (ORCID:0000000307847987), Epstein, Charles B. [Broad Institute, Cambridge, MA (United States)] (ORCID:0000000183588345), Gaskell, Elizabeth [Broad Institute, Cambridge, MA (United States)], Bernstein, Bradley E. [Broad Institute, Cambridge, MA (United States)] (ORCID:0000000257266278), Dickel, Diane E. [Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)], Visel, Axel [Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); USDOE Joint Genome Institute (JGI), Berkeley, CA (United States); Univ. of California, Merced, CA (United States)] (ORCID:0000000241307784), Pennacchio, Len A. [Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)] (ORCID:0000000287483732), Mortazavi, Ali [Univ. of California, Irvine, CA (United States)] (ORCID:0000000242596362), Kundaje, Anshul [Stanford Univ., CA (United States)] (ORCID:0000000330842287), Weng, Zhiping [Univ. of Massachusetts, Worchester, MA (United States). UMass Chan Medical School] (ORCID:0000000230327966). 2026-01-07. An expanded registry of candidate cis -regulatory elements. https://doi.org/10.1038/s41586-025-09909-9
Cite the original work for its findings. Save a collection to share your selection of sources.