| name | seqeron-epigenetics |
| description | Analyze DNA methylation and chromatin state with Seqeron (MCP tools OR the C# API). Use to find CpG sites / CpG islands (Gardiner-Garden & Frommer) and CpG observed/expected ratio, classify CpG/CHG/CHH methylation contexts, call per-CpG methylation from bisulfite sequencing reads (Bismark-style) or forward-simulate bisulfite conversion, aggregate a weighted methylation profile, find differentially methylated regions (DMRs) between two samples (methylKit tiling windows + Fisher exact), estimate epigenetic age (Horvath DNA-methylation clock), predict chromatin state / annotate histone modifications (ChromHMM-style H3K4me3/H3K4me1/H3K27ac/H3K36me3/H3K27me3/H3K9me3), find accessible (ATAC-seq-like) chromatin regions, and predict imprinted genes from allele-specific methylation. Triggers: "find CpG islands", "CpG O/E ratio", "call methylation from bisulfite", "bisulfite-convert this sequence", "methylation profile", "find DMRs between groups", "hyper/hypomethylated regions", "epigenetic age / DNAm age / methylation clock", "predict chromatin state", "annotate histone marks", "accessible chromatin peaks", "imprinted genes". Input is DNA (methylation β-values / read piles for the calling tools). Server: annotation (all EpigeneticsAnalyzer.*). |
| allowed-tools | Read, Bash, Grep, Glob |
seqeron-epigenetics — methylation, bisulfite, DMRs, chromatin, epigenetic age
Routing + orchestration skill for the epigenetics / DNA-methylation family on the annotation
server (13 tools, one backing class: EpigeneticsAnalyzer.*). It picks the right tool for a
CpG / methylation / bisulfite / DMR / chromatin / epigenetic-age question and gives a dual-mode
recipe (MCP tool name and the equivalent Seqeron.Genomics C# Method ID).
- Rigor is delegated. Tool-only computation, provenance, envelope, cross-check, units, 0-based
coords, and the alpha / not-for-clinical caveat are owned by
bio-rigor — it applies by default; do not restate.
- Don't know a tool name? Use
seqeron-discovery
(python3 scripts/skills/find-tool.py <kw> --server annotation) — never guess.
- Point, don't duplicate. Full I/O schemas live in
docs/mcp/tools/annotation/*.md;
algorithm invariants/formulas in docs/algorithms/Epigenetics/*.md.
Scope boundary — this family vs neighbours
- This skill OWNS the DNA-methylation / chromatin family: CpG sites/islands/O-E, methylation
contexts (CpG/CHG/CHH), bisulfite calling + simulation, methylation profiles, DMRs, epigenetic
age, chromatin-state / histone-mark annotation, accessible regions, imprinted genes.
bio-annotation name-drops this family shallowly — route here.
- Everything else annotation (ORFs/genes/promoters, variant calling & effect, motifs/PWMs,
repeats/low-complexity, k-mers, splicing, miRNA, RNA-seq) stays in
bio-annotation.
- Heterochromatin blocks / G-bands at chromosome scale →
find_heterochromatin_regions
(chromosome server) via bio-chromosome — distinct from the
per-locus predict_chromatin_state/Heterochromatin label here.
- No nucleosome-positioning and no enhancer-caller tool exists. Enhancer states
(Active/Weak/Bivalent enhancer) fall out of
predict_chromatin_state; there is no
standalone nucleosome/enhancer tool — do not fabricate one.
Decision guide — which tool for which question
| Question | Tool ([MCP] / Method ID) |
|---|
| Positions of every CpG dinucleotide | find_cpg_sites / EpigeneticsAnalyzer.FindCpGSites |
| CpG observed/expected ratio for one sequence | cpg_observed_expected / EpigeneticsAnalyzer.CalculateCpGObservedExpected |
| CpG islands (GC ≥ minGc and O/E ≥ minCpGRatio, merged) | find_cpg_islands / EpigeneticsAnalyzer.FindCpGIslands |
| Classify C into CpG / CHG / CHH context (sequence-only) | find_methylation_sites / EpigeneticsAnalyzer.FindMethylationSites |
| Forward-simulate bisulfite conversion of a strand | simulate_bisulfite_conversion / EpigeneticsAnalyzer.SimulateBisulfiteConversion |
| Call per-CpG methylation level from bisulfite reads | methylation_from_bisulfite / EpigeneticsAnalyzer.CalculateMethylationFromBisulfite |
| Aggregate sites → weighted global/CpG/CHG/CHH profile | methylation_profile / EpigeneticsAnalyzer.GenerateMethylationProfile |
| DMRs between two samples (hyper/hypomethylated) | find_dmrs / EpigeneticsAnalyzer.FindDMRs |
| Epigenetic (DNAm) age from clock CpGs | epigenetic_age / EpigeneticsAnalyzer.CalculateEpigeneticAge |
| Chromatin state from six histone marks | predict_chromatin_state / EpigeneticsAnalyzer.PredictChromatinState |
| Per-interval state from a single histone mark | annotate_histone_modifications / EpigeneticsAnalyzer.AnnotateHistoneModifications |
| Accessible (ATAC-seq-like) chromatin peaks | find_accessible_regions / EpigeneticsAnalyzer.FindAccessibleRegions |
| Imprinted genes from allele-specific methylation | predict_imprinted_genes / EpigeneticsAnalyzer.PredictImprintedGenes |
Coordinates 0-based; island end is exclusive. Methylation levels & β-values are fractions
0..1; histone/accessibility signals 0..1 (out-of-range signal throws for predict_chromatin_state).
Confirm exact I/O per tool doc.
Canonical dual-mode pipelines
(a) CpG islands + independent O/E cross-check
- [MCP]
find_cpg_islands(sequence, minLength?=200, minGc?=0.5, minCpGRatio?=0.6) → islands[] (0-based start, exclusive end, gcContent, cpGRatio).
- [MCP] for a reported island, re-derive its ratio independently:
cpg_observed_expected(sequence=island_substring) → ratio should match cpGRatio.
- [C# API]
EpigeneticsAnalyzer.FindCpGIslands(...) → .CalculateCpGObservedExpected(...).
Provenance
1) find_cpg_islands(sequence,minLength=200,minGc=0.5,minCpGRatio=0.6) → islands[]
2) cpg_observed_expected(island_substr) → ratio ≈ island.cpGRatio (independent recompute)
Caveat: alpha — validate before use.
(b) Bisulfite reads → per-CpG methylation → profile
- [MCP]
methylation_from_bisulfite(referenceSequence, bisulfiteReads=[{readSequence,startPosition}]) → sites[] (position, type=CpG, methylationLevel, coverage); uncovered CpGs omitted.
- [MCP]
methylation_profile(sites) → weighted globalMethylation/cpGMethylation/cHGMethylation/cHHMethylation, totalCpGSites, methylatedCpGSites, methylationByPosition.
- Optional round-trip check:
simulate_bisulfite_conversion(referenceSequence, methylatedPositions) forward-models the reads you then call — a self-consistency oracle.
- [C# API]
EpigeneticsAnalyzer.CalculateMethylationFromBisulfite(...) → .GenerateMethylationProfile(...); .SimulateBisulfiteConversion(...).
Provenance
1) methylation_from_bisulfite(ref,reads) → per-CpG sites (level=meC/(meC+unmeC), coverage=C/T calls)
2) methylation_profile(sites) → weighted per-context levels (Schultz 2012)
Cross-check: simulate_bisulfite_conversion(ref,methylatedPositions) reproduces the read pile.
Caveat: alpha.
(c) DMRs between two samples
- Build each sample's
sites[] (from pipeline (b), or caller-supplied).
- [MCP]
find_dmrs(sample1=control, sample2=treatment, windowSize?=1000, minDifference?=0.25, minCpGCount?=3) → regions[] (meanDifference=mean(s2−s1), Fisher pValue, cpGCount, annotation=Hyper/Hypomethylated).
- [C# API]
EpigeneticsAnalyzer.FindDMRs(...). Direction is sample2 − sample1 — pass control first. p is two-sided Fisher on pooled counts, not multiple-testing corrected. (Provenance block → reference/pipelines.md §3.)
(d) Chromatin state from histone marks (+ accessibility)
- [MCP]
predict_chromatin_state(h3k4me3,h3k4me1,h3k27ac,h3k36me3,h3k27me3,h3k9me3) → state (ChromHMM-priority: Bivalent* → Active* → Transcribed → Repressed → Heterochromatin → LowSignal). Signals must be 0..1.
- [MCP] per-interval single-mark labels:
annotate_histone_modifications(modifications=[{start,end,mark,signal}]) → annotations[] with predictedState.
- [MCP] accessible peaks:
find_accessible_regions(accessibilitySignal=[{position,signal}], threshold?=0.5, minWidth?=100, maxGap?=50) → regions[] (accessibilityScore, peakType Strong/Moderate/Weak).
- [C# API]
.PredictChromatinState(...) · .AnnotateHistoneModifications(...) · .FindAccessibleRegions(...).
(e) Epigenetic age (Horvath clock)
- [MCP]
epigenetic_age(methylationAtClockCpGs={cpgId→β}, coefficients={cpgId→coef}, intercept?=0.0) → age (years, Horvath inverse calibration, adult.age=20). CpGs missing from either side contribute nothing.
- [C# API]
EpigeneticsAnalyzer.CalculateEpigeneticAge(...). You supply the published clock coefficient table (wrapper is clock-agnostic) — the result is only as good as that table. (Provenance block → reference/pipelines.md §6.)
Envelope
No epigenetics unit is a guarded unit in docs/Validation/LIMITATIONS.md (no EpigeneticsAnalyzer.* MinimumMode guard; verified 2026-07). So there is no STOP rule specific to this family — but the algorithms are model/heuristic-based (Gardiner-Garden & Frommer thresholds, ChromHMM present/absent binarization at 0.5, methylKit tiling, Horvath calibration). Report results as model output under the stated parameters/thresholds, not ground truth, and keep the alpha / not-for-clinical caveat from bio-rigor. Rule-out results (empty islands/regions/imprinted) are threshold-dependent — record the parameters used.
End-to-end grounded example
Task. From a reference and a pile of bisulfite reads for two conditions, characterise methylation
and find DMRs, cross-checking each layer.
find_cpg_sites(referenceSequence) → CpG positions (the set DMR windows are built over). (.FindCpGSites)methylation_from_bisulfite(referenceSequence, controlReads) and again with treatmentReads → two sites[]. (.CalculateMethylationFromBisulfite)methylation_profile(each sites[]) → per-condition weighted CpG methylation (sanity summary). (.GenerateMethylationProfile)find_dmrs(control_sites, treatment_sites, windowSize=1000, minDifference=0.25, minCpGCount=3) → regions[]. (.FindDMRs)- Cross-check: each DMR's
cpGCount and window bounds must fall within the CpG positions from step 1, and meanDifference sign must agree with the two profile levels from step 3.
Provenance
1) find_cpg_sites(ref) → CpG positions
2) methylation_from_bisulfite(ref, controlReads|treatmentReads) → sites per condition
3) methylation_profile(sites) → weighted per-context methylation (cross-check magnitudes)
4) find_dmrs(control,treatment,windowSize=1000,minDifference=0.25,minCpGCount=3) → Hyper/Hypomethylated regions + Fisher p
5) Cross-check: DMR windows ⊆ step-1 CpGs; meanDifference sign agrees with step-3 profiles
Caveat: alpha; thresholds/params are model choices — Fisher p not multiple-testing corrected. Not for clinical use.
Reference
