Understanding CIRCE Co-accessibility Scores¶
CIRCE computes a co-accessibility score for each pair of genomic regions, summarizing how strongly their accessibility varies together across single cells. These scores help identify regulatory relationships, shared chromatin contexts, and coordinated patterns of chromatin opening and closing.
Co-accessibility scores generally range from –1 to +1, where the sign and magnitude reflect how consistently the two regions share accessibility states.
Positive scores¶
A positive co-accessibility score indicates that two regions tend to be accessible in the same cells and inaccessible in the same cells.
Biologically, this pattern can arise from:
Shared regulatory activity
Distal enhancers, promoters, or other regulatory elements may be active in the same cell populations and therefore open together. This often reflects coordinated transcription factor binding or shared participation in a regulatory program.Chromatin architecture
Regions within the same chromatin loop, sub-domain, or regulatory neighborhood frequently adopt similar accessibility states across cells. A positive score is a statistical signature of being in a shared 3D context, even though it does not directly measure chromatin contacts.Cell-state–dependent activation
During differentiation or stimulus responses, groups of regulatory elements can turn on together. Positive scores highlight these co-activated modules.
What positive scores do not imply¶
A positive score does not mean that the two regions have identical biological roles. Co-accessible elements:
do not necessarily regulate the same gene,
may have unequal or unrelated regulatory impact,
may use different transcription factors,
do not guarantee physical interaction.
Thus, co-accessibility reflects coordinated behavior across cells, not equivalence of function.
Negative scores¶
A negative co-accessibility score means that when one region is accessible in a given cell, the other tends to be inaccessible. This can arise from:
Mutually exclusive regulatory programs
For example, two enhancers used in distinct lineages or cell states.Switch-like behavior
Elements that participate in alternative regulatory modes during differentiation or branching trajectories.
Negative scores generally occur less frequently and can be harder to interpret; they do not imply repression or antagonism, only opposite accessibility patterns across cells.
What co-accessibility tells you — and what it does not¶
Co-accessibility scores capture the population-level coordination of chromatin accessibility. They are useful for generating hypotheses about regulatory architecture and for linking distal elements to possible targets.
However, co-accessibility alone does not confirm:
direct enhancer–gene regulation,
causal influence on gene expression,
physical chromatin looping,
functional equivalence between elements.
Integrating co-accessibility with additional evidence (expression, motif enrichment, 3D contact data, etc.) provides stronger regulatory interpretation.
Summary¶
Co-accessibility scores quantify how similarly two genomic regions behave across single cells.
Positive scores reflect coordinated accessibility and shared regulatory context.
Negative scores indicate mutually exclusive or divergent accessibility patterns.
Co-accessibility is a descriptive signal and does not, by itself, establish direct regulatory effects.
These scores help map the structure and dynamics of the regulatory landscape, guiding downstream interpretation and hypothesis generation.
Sources¶
Pliner,H.A. et al. (2018) Cicero predicts cis-regulatory DNA interactions from single-cell chromatin accessibility data. Mol. Cell, 71, 858-871.e8. https://doi.org/10.1016/j.molcel.2018.06.044
Trimbour,R. et al. (2026) CIRCE: a scalable Python package to predict cis-regulatory DNA interactions from single-cell chromatin accessibility data. Bioinformatics, 42(3), btag092. https://doi.org/10.1093/bioinformatics/btag092