AetherXeno

AetherXeno maps how non-coding regulatory variants change binding at the hepatic xenobiotic receptors PXR, FXR and AhR. The scores are built on primary human hepatocyte ChIP-seq of each receptor in its ligand activated, induced state, treated with rifampicin for PXR, the FXR agonist GW4064 and the AhR ligand TCDD, not a generic resting map. Every variant is cross-linked to ClinVar, GTEx liver eQTLs, GWAS and PharmGKB, and curated pharmacogenes carry a pharmacist reviewed causal layer called CAMIP.

PXR FXR AhR

Try a variant id like chr20_54107677_C_A or a gene like CYP3A4.

Image by kjpargeter on Freepik

How it works

From an induced binding map, to scored variants, to a reviewed causal layer. Select a stage to see what it does.

Step 1 of 5
Drug induction ChIP-seq

Primary human hepatocytes are treated with rifampicin for PXR, the FXR agonist GW4064 and the AhR ligand TCDD. ChIP-seq then maps where each receptor binds in that induced, ligand activated state.

drug activatesthe receptorreceptor bindsa DNA elementChIP-seq mapsthe binding

What a score means

Each score is ALT minus REF. The model predicts receptor binding for the reference sequence and for the sequence carrying the variant, then sums the difference across the central bins. One score per receptor.

ACGTGCATresponse elementVariant in a regulatory elementREFALTPredicted binding, REF vs ALTΔ = ALT − REFnegative loss (LoF) · positive gain (GoF)One Δ per receptor: PXR, FXR, AhR

The CAMIP causal chain

For curated pharmacogenes, each chain explains how a regulatory variant can reach a drug, in mechanism only.

Regulatory variantin a receptor elementReceptor binding fallsPXR / FXR / AhREnzyme or transporterinduction is bluntedDrug exposure shiftsinteraction riskMechanism only, confirmed by a reviewing pharmacist. Affected drugs are mapped from PharmGKB.

What is inside

17,267,831 scored variant effects, one row for every possible single base substitution inside a receptor regulatory element, each with a score for PXR, FXR and AhR.

8,691 regulatory elements: the top ChIP-seq peak summits by signal, used as the scored regions, up to 3,000 per receptor.

28,227 atlas variants also carry a ClinVar clinical annotation joined onto their receptor scores.

18,560 variants fall inside the high priority receptor peak tiers used for the curated analyses.

Regulatory elements per receptor

PXR3,000

scored regulatory elements

FXR2,947

scored regulatory elements

AhR2,744

scored regulatory elements

Each element is a top ChIP-seq peak summit by signal, capped at 3,000 per receptor.

How the predictions are checked

The atlas is checked against independent data the model never trained on. What each check looks at is below; the full quantitative benchmarks are reported in the paper.

Gold-standard recovery

Known functional PXR luciferase response SNPs rank among the most strongly scored variants in their regions, so the model recovers established response elements.

Liver eQTL agreement

Variants the model scores highly are enriched for being GTEx liver eQTLs, an expression readout never seen in training. Browse them on the Evidence page.

Motif grammar

The bases the model is most sensitive to concentrate on known nuclear-receptor sequence motifs such as RXRA and NR1I2, rather than on flanking DNA.

Full benchmark statistics are in the paper. See the Documentation for methods.