The Registry of Candidate cis-Regulatory Elements (cCREs)

The Registry of cCREs is a genome-wide catalog of candidate regulatory elements defined using chromatin accessibility, histone modification, and transcription factor binding data generated by ENCODE. The Registry is designed to be comprehensive, cell type–agnostic, and extensible as new data become available

Element Anchors

In ENCODE4, cCREs are anchored using multiple complementary strategies to capture a broad spectrum of regulatory elements:

• Representative DNase hypersensitive sites (rDHSs), generated by clustering DNase-seq peaks across large numbers of biosamples, define the majority of accessible regulatory regions.
• Transcription factor clusters, representing reproducible transcription factor binding sites that do not overlap DNase hypersensitive regions, capture regulatory elements with low chromatin accessibility but strong, protein-binding signatures.
• Multi-mapper rDHSs, derived from alignments that retain multi-mapping reads, recover regulatory elements in recently duplicated or repetitive genomic regions that were underrepresented in earlier Registry versions.

Together, these anchors define millions of candidate regulatory elements in the human and mouse genomes.

Quantifying Epigenomic Signals

For each cCRE anchor, we compute standardized signal summaries for chromatin accessibility (DNase-seq or ATAC-seq), histone modifications (H3K4me3 and H3K27ac), and CTCF binding across all available biosamples. Signals are converted to Z-scores within each biosample to ensure comparability across assays and experiments. These standardized signals form the basis for both classification and biosample-specific activity annotations.

cCREs defined using multi-mapping–inclusive chromatin accessibility data do not have associated epigenomic signal tracks, as the full set of ENCODE assays was not reprocessed using multi-mapping–inclusive alignments. These elements are therefore included in the Registry as candidate regulatory elements but lack quantitative signal annotations.

Cell Type–Agnostic Classification of cCREs

Each cCRE is assigned a cell type–agnostic class based on its dominant biochemical signatures across all surveyed biosamples and its proximity to annotated transcription start sites (TSSs). This classification is intended to be analogous to gene catalogs, which define genes independently of their expression levels in individual cell types.

The major cCRE classes include:

All signal values used for classification are retained and made available in SCREEN to support custom filtering and user-defined analyses.

Core, Partial, and Ancillary Collections

Because the availability of epigenomic assays varies across biosamples, SCREEN organizes biosample-specific annotations into three collections:

• Core Collection: Biosamples with chromatin accessibility, H3K4me3, H3K27ac, and CTCF data. These provide the most complete and highest-confidence cCRE annotations and are recommended for most analyses.
• Partial Data Collection: Biosamples with chromatin accessibility and a subset of additional marks. These samples enable high-resolution boundary definition but support a reduced set of cCRE classes.
• Ancillary Collection: Biosamples lacking chromatin accessibility data. In these cases, cCREs are annotated only by the presence or absence of high signal for available assays, and users are advised to anchor analyses on cCREs defined in the Core or Partial collections.

SCREEN clearly labels biosamples by collection to guide appropriate interpretation.

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