{"data":{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:38512414", "kind": "science-record", "revision": 3, "content_hash": "sha256:16a9ed423a603e7e742ffad928e836f043b1c9fed78bfd8fb38d0738c4460ddb", "created_at": "2026-11-01T19:20:27Z", "updated_at": "2026-11-01T21:32:44Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity.", "doi": "10.1007/s00125-024-06123-6", "pmid": "38512414", "authors": ["Vanessa Yu", "Fiona Yong", "Angellica Marta", "Sanjay Khadayate", "Adrien Osakwe", "Supriyo Bhattacharya", "Sneha S Varghese", "Pauline Chabosseau", "Sayed M Tabibi", "Keran Chen", "Eleni Georgiadou", "Nazia Parveen", "Mara Suleiman", "Zoe Stamoulis", "Lorella Marselli", "Carmela De Luca", "Marta Tesi", "Giada Ostinelli", "Luis Delgadillo-Silva", "Xiwei Wu", "Yuki Hatanaka", "Alex Montoya", "James Elliott", "Bhavik Patel", "Nikita Demchenko", "Chad Whilding", "Petra Hajkova", "Pavel Shliaha", "Holger Kramer", "Yusuf Ali", "Piero Marchetti", "Robert Sladek", "Sangeeta Dhawan", "Dominic J Withers", "Guy A Rutter", "Steven J Millership"], "journal": "Diabetologia", "year": 2024, "abstract": "AIMS/HYPOTHESIS: Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. These include a subpopulation of highly connected 'hub' cells, important for the propagation of intercellular Ca2+ waves. Functional subpopulations have also been demonstrated in human beta cells, with an altered subtype distribution apparent in type 2 diabetes. At present, the molecular mechanisms through which beta cell hierarchy is established are poorly understood. Changes at the level of the epigenome provide one such possibility, which we explore here by focusing on the imprinted gene Nnat (encoding neuronatin [NNAT]), which is required for normal insulin synthesis and secretion.\nMETHODS: Single-cell RNA-seq datasets were examined using Seurat 4.0 and ClusterProfiler running under R. Transgenic mice expressing enhanced GFP under the control of the Nnat enhancer/promoter regions were generated for FACS of beta cells and downstream analysis of CpG methylation by bisulphite sequencing and RNA-seq, respectively. Animals deleted for the de novo methyltransferase DNA methyltransferase 3 alpha (DNMT3A) from the pancreatic progenitor stage were used to explore control of promoter methylation. Proteomics was performed using affinity purification mass spectrometry and Ca2+ dynamics explored by rapid confocal imaging of Cal-520 AM and Cal-590 AM. Insulin secretion was measured using homogeneous time-resolved fluorescence imaging.\nRESULTS: Nnat mRNA was differentially expressed in a discrete beta cell population in a developmental stage- and DNA methylation (DNMT3A)-dependent manner. Thus, pseudo-time analysis of embryonic datasets demonstrated the early establishment of Nnat-positive and -negative subpopulations during embryogenesis. NNAT expression is also restricted to a subset of beta cells across the human islet that is maintained throughout adult life. NNAT+ beta cells also displayed a discrete transcriptome at adult stages, representing a subpopulation specialised for insulin production, and were diminished in db/db mice. 'Hub' cells were less abundant in the NNAT+ population, consistent with epigenetic control of this functional specialisation.\nCONCLUSIONS/INTERPRETATION: These findings demonstrate that differential DNA methylation at Nnat represents a novel means through which beta cell heterogeneity is established during development. We therefore hypothesise that changes in methylation at this locus may contribute to a loss of beta cell hierarchy and connectivity, potentially contributing to defective insulin secretion in some forms of diabetes.\nDATA AVAILABILITY: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD048465.", "claims": [{"id": "claim-method", "statement": "Data were assessed using GraphPad Prism 9.0, with <5% error probability considered significant (i.e. p<0.05).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38512414", "locator": "sections[14] \"Statistical analysis\" paragraph 2", "quote": "Data were assessed using GraphPad Prism 9.0, with <5% error probability considered significant (i.e. p<0.05)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "RNA-seq data are available from the GEO under accession number GSE249659. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD048465. ImageJ scripts and CellProfiler pipelines can be made available upon reasonable request. Pseudo-time analysis scripts are available via GitHub using the link https://github.com/aosakwe/Pseudotime_Analysis_MouseIslets. Transcriptomic data for ob/ob mice can be obtained from a publicly available source from the Alan Attie laboratory (http://diabetes.wisc.edu/search).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38512414", "locator": "sections[28] \"notes\" paragraph 1", "quote": "RNA-seq data are available from the GEO under accession number GSE249659. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD048465. ImageJ scripts and CellProfiler pipelines can be made available upon reasonable request. Pseudo-time analysis scripts are available via GitHub using the link https://github.com/aosakwe/Pseudotime_Analysis_MouseIslets. Transcriptomic data for ob/ob mice can be obtained from a publicly available source from the Alan Attie laboratory (http://diabetes.wisc.edu/search)."}], "state": "complete"}, {"id": "claim-target-result", "statement": "These findings demonstrate that differential DNA methylation at Nnat represents a novel means through which beta cell heterogeneity is established during development.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:38512414", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "These findings demonstrate that differential DNA methylation at Nnat represents a novel means through which beta cell heterogeneity is established during development."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "These findings demonstrate that differential DNA methylation at Nnat represents a novel means through which beta cell heterogeneity is established during development.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:38512414"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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Pseudo-time analysis scripts are available via GitHub using the link https://github.com/aosakwe/Pseudotime_Analysis_MouseIslets. 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METHODS: Single-cell RNA-seq datasets were examined using Seurat 4.0 and"], "order_basis": "paper_text_order:853", "id": "assay:1"}, {"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["ynthesis and secretion. METHODS: Single-cell RNA-seq datasets were examined using Seurat 4.0 and", "CpG methylation by bisulphite sequencing and RNA-seq, respectively. Animals deleted for the de no", ". NNAT+ beta cells also displayed a discrete transcriptome at adult stages, representing a subpopulatio"], "order_basis": "paper_text_order:865", "id": "assay:2"}, {"role": "data_generation", "definition_id": "flow_cytometry", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["enhancer/promoter regions were generated for FACS of beta cells and downstream analysis of CpG"], "order_basis": "paper_text_order:1065", "id": "assay:3"}, {"role": "data_generation", "definition_id": "mass_spectrometry", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["cs was performed using affinity purification mass spectrometry and Ca2+ dynamics explored by rapid confocal", "me forms of diabetes. DATA AVAILABILITY: The mass spectrometry proteomics data have been deposited to the P", "to explore control of promoter methylation. Proteomics was performed using affinity purification ma", "es. DATA AVAILABILITY: The mass spectrometry proteomics data have been deposited to the ProteomeXcha"], "order_basis": "paper_text_order:1360", "id": "assay:4"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["rial (ESM) Methods. Animal models Transgenic mouse lines expressing Cre recombinase under the c", "P) expression were purchased from the Mutant Mouse Resource and Research Centre (MMRRC, USA) re", "ing Cre recombinase under the control of the rat insulin promoter (RIP) [43] and with a tdTom", ", RNA silencing and GSIS Human EndoC-βH1 and rat INS1E beta cells were cultured as previously"], "order_basis": "paper_text_order:3039", "id": "assay:5"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.77, "evidence": ["ressing an NNAT-targeting short hairpin RNA (shRNA; Sigma-Aldrich) or Silencer Select siRNAs (A"], "order_basis": "paper_text_order:3933", "id": "assay:6"}]},"meta":{"api_version":"v1","automation_ladder_snapshot":"ba34b49490d9bfaf","automation_ladder_caveats":["Method extraction is rule-based and has no hand-judged accuracy sample. 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The citation term of the ranking is inert here, and the shortlist is ordered by publication type alone.","status":"unverified","severity":"high"},{"code":"abstract_absent","basis":["1,667 of 5,529 records (30.2%) carry no abstract at all."],"claim":"Evidence base for classification","gloss":"Some records contain a title and publication type only, defining the available classification evidence.","detail":"Where the mirror contains a title and publication types only, those fields define the classifier evidence. 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Model comparison begins when a working API credential is connected and measured.","status":"not_measured","severity":"high"},{"code":"confidence_is_a_band","basis":["low band: 135 of 210 hand-judged records were correct, 64.3% [57.6, 70.5] (95% CI).","medium band: 80 of 104 hand-judged records were correct, 76.9% [68.0, 84.0] (95% CI).","high band: 73 of 76 hand-judged records were correct, 96.0% [89.0, 98.7] (95% CI).","A fitted calibrated probability was built, measured and withdrawn: it overstated held-out accuracy and reorders nothing."],"claim":"Confidence band and evidence score","gloss":"The confidence band carries a measured accuracy interval; 0.85 represents relative rank strength.","detail":"Confidence on this run is a BAND plus its measured accuracy interval. The number stored alongside each record is a monotone evidence score that orders records; 0.85 represents relative rank strength. A fitted probability was withdrawn after it overstated held-out accuracy. Threshold on the band.","status":"measured","severity":"medium"},{"code":"three_way_split_is_diagnostic","basis":["The corpus is published at the two-way decision: automatable or not-automatable. The three-way split (data_only / physical / mixed) is published as a diagnostic with its measured reliability attached, not as a claim, because the rule engine's `mixed` call cannot be defended.","The engine called 22 record(s) mixed; 10 matched the human judgement (45.5%, 95% CI 26.9-65.3).","The engine's `mixed` call is right on 10/22 hand-judged records (45.5%, 95% CI 26.9%-65.3%); a constant `physical` guess scores 36.4%.","The engine's `mixed` call does not reliably beat a constant `physical` guess on the hand-judged records it labels mixed.","The sign of that difference flips between two independent samples, so the three-way refinement is not demonstrably informative.","The mixed stratum contributes a disproportionate share of errors relative to its size.","At title-only depth the physical/mixed split collapses: a title says that work was done, not whether it was also analysed."],"claim":"The published decision is two-way","gloss":"The three-way split is shown for diagnosis only. The published split is two ways.","detail":"Count and filter the corpus on automatable versus not-automatable. The data_only / physical / mixed split remains an internal engine diagnostic because the mixed call has lower measured reliability.","status":"measured","severity":"medium"},{"code":"automatable_flag_unproven","basis":["6 of 29 assay families are marked automatable now: meta_analysis, machine_learning, survival_analysis, pca, molecular_docking, differential_expression.","The flag is a rule over assay family and work type; validation begins with the first executed replication.","It inherits the 75.2% data_only agreement rate, because the flag requires the record to be analysis-only."],"claim":"Automatable now","gloss":"This flag marks assay families the rules classify as data-only. The first executed replication will validate it.","detail":"This flag marks families the rules consider replicable from data alone. Its validity depends on the analysis-only classification and will be measured through an executed replication.","status":"unverified","severity":"medium"}],"confidence_policy":"band_with_measured_interval","confidence_contract":{"policy":"band_with_measured_interval","summary":"Confidence is reported as a BAND with a measured accuracy interval. The raw evidence score supplies monotone ordering. A fitted point estimate was withdrawn after it overstated held-out accuracy.","evidence_score":"A monotone evidence score in [0,1] built from cue mass, axis separation and text coverage. Use it to order records. Interpret 0.85 as relative rank strength.","confidence_band":"low | medium | high. Consumers threshold on this value.","band_accuracy":"Wilson 95% interval on the measured agreement of the hand-judged records in this band.","calibrated_confidence":"WITHDRAWN. Reintroduction requires held-out evidence demonstrating reliable estimates across every bin."},"band_accuracy":{"low":{"n":210,"low":0.576,"band":"low","high":0.7046,"agree":135,"accuracy":0.6429},"high":{"n":76,"low":0.8903,"band":"high","high":0.9865,"agree":73,"accuracy":0.9605},"medium":{"n":104,"low":0.6795,"band":"medium","high":0.8397,"agree":80,"accuracy":0.7692}},"provider":"rule_based_v1+lex99e1195c7d6f","lexicon_id":"99e1195c7d6f","contract_published_at":"2026-10-23T12:25:29.022232+00:00","confidence_is_band":true,"confidence_is_probability":false,"decision_taxonomy":"two_way","decidable_fraction_two_way":0.8854,"decidable_fraction_two_way_low":0.8565,"decidable_fraction_two_way_high":0.9143,"decidable_fraction_three_way":0.8586,"decidable_fraction_three_way_low":0.8287,"decidable_fraction_three_way_high":0.8884,"decidable_population":5529,"validation_sample_size":438,"three_way_cost_fraction":0.0268,"three_way_cost_records":148,"decision_counts":{"automatable":230,"not_automatable":5299},"decision_split":{"automatable":{"count":230,"share":0.04159884246699222},"not_automatable":{"count":5299,"share":0.9584011575330078}},"diagnostic_work_type_counts":{"mixed":24,"physical":5275,"data_only":230}}}