An expanded registry of candidate cis-regulatory elements

Mammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression<sup>1</sup>. 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<sup>2</sup>. 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<sup>3</sup>, massively parallel reporter assay<sup>4</sup>, CRISPR perturbation<sup>5,6</sup> and transgenic mouse assays<sup>7</sup> 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.

Authors

Institutions

Publication Details

Journal
Nature
Published
2026-01-07
DOI
https://doi.org/10.1038/s41586-025-09909-9
Citations
8
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
177.90
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

An expanded registry of candidate cis-regulatory elements

Jonathan A. D. Fisher, Charles B. Epstein, Axel Visel, Anusri Pampari et al.
8 citations
Nature
Genomics and Chromatin Dynamics
177.90
article

An expanded registry of candidate cis-regulatory elements

Jonathan A. D. Fisher, Charles B. Epstein, Axel Visel, Anusri Pampari, M. Gerstein, Annika K. Weimer, Timothy E. Reddy, Diane E. Dickel, Timur R. Galeev, L Pennacchio, Milad Razavi-Mohseni, Elizabeth Gaskell, Xuezhu Yu, Vivekanandan Ramalingam, Mats Ljungman, B Bernstein, Nishigandha Phalke, M Beer, C. J. Ramírez, Ross Swofford, Beatrice Borsari, Mu-Yun Gao, Anshul Kundaje, J. Russell Moore, Eve S. Wattenberg, Shaimae I. Elhajjajy, Mary E. Likhite, Nicole Shedd, Y. Fu, J Engreitz, Zhiping Weng, Andrés Colubri, Nina Farrell, Mansi Khandpekar, Matthew C Lacadie, Mohit Ganna, Eva Choudhury, Fairlie Reese, Huong Phan, Gregory Andrews, Roderic Guigó, Michael P. Snyder, Marina Ruiz-Romero, Jair Meza, Henry E. Pratt, Jinrui Xu, Kaili Fan, Ali Mortazavi, Maxwell Campbell
article en
8 citations

Abstract

Mammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression<sup>1</sup>. 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<sup>2</sup>. 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<sup>3</sup>, massively parallel reporter assay<sup>4</sup>, CRISPR perturbation<sup>5,6</sup> and transgenic mouse assays<sup>7</sup> 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.

Nature
Broad Institute (US), UMass Memorial Health Care (US), Lucile Packard Children's Hospital (US), Howard University (US), Johns Hopkins University (US), Lawrence Berkeley National Laboratory (US), University of California, Merced (US), University of Massachusetts Chan Medical School (US), Universitat Pompeu Fabra (ES), Duke University (US), Joint Genome Institute (US), University of California, Irvine (US), Cardiovascular Institute of the South (US), University of Michigan (US), Foundation Center (US), Yale University (US), Novo Nordisk (United States) (US), Centre for Genomic Regulation (ES), UMass Memorial Medical Center (US), Stanford University (US)
Openalex Percentile: Top 0%
Genomics and Chromatin Dynamics
177.90
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.