An expanded registry of candidate cis-regulatory elements
J. Russell Moore, Henry E. Pratt, Kaili Fan, Nishigandha Phalke, Jonathan A. D. Fisher, Shaimae I. Elhajjajy, Gregory Andrews, Mingshi Gao, Nicole Shedd, Y. Fu, Matthew C Lacadie, Jair Meza, Mansi Khandpekar, Mohit Ganna, Eva Choudhury, Ross Swofford, Huong Phan, C. J. Ramírez, Maxwell Campbell, Mary E. Likhite, Nina Farrell, Annika K. Weimer, Anusri Pampari, Vivekanandan Ramalingam, Fairlie Reese, Beatrice Borsari, Xuezhu Yu, Eve S. Wattenberg, Marina Ruiz-Romero, Milad Razavi-Mohseni, Jinrui Xu, Timur R. Galeev, Andrés Colubri, M Beer, Roderic Guigó, M. Gerstein, J Engreitz, Mats Ljungman, Timothy E. Reddy, Michael P. Snyder, Charles B. Epstein, Elizabeth Gaskell, B Bernstein, Diane E. Dickel, Axel Visel, L Pennacchio, Ali Mortazavi, Anshul Kundaje, Zhiping Weng
Abstract
Abstract Mammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression 1 . 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 2 . 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 3 , massively parallel reporter assay 4 , CRISPR perturbation 5,6 and transgenic mouse assays 7 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.