{"doi":"10.1101/2022.05.06.490953","title":"DNA methylation Dependent Restriction of Tyrosine Hydroxylase Contributes to Pancreatic <i>β</i> -cell Heterogeneity","abstract":"Abstract The molecular and functional heterogeneity of pancreatic β -cells is well recognized. Pancreatic islets harbor a small subset of β -cells that co-express Tyrosine Hydroxylase (TH), an enzyme involved in synthesis of catecholamines that repress insulin secretion. Restriction of this sub-population within islets is essential for appropriate insulin secretion. However, the distinguishing characteristics of this subpopulation and the mechanisms that restrict TH expression in β -cells are not known. Here, we define the specific molecular and metabolic characteristics of the TH+ β -cells and show that TH expression in β -cells is restricted by DNA methylation patterning during β -cell lineage specification. Ablation of de novo DNA methyltransferase Dnmt3a in the pancreatic- and endocrine-progenitor lineages results in a dramatic increase in the proportion of TH+ β -cells, while β -cell specific ablation of Dnmt3a has no effect on this sub-population. We demonstrate that maintenance of Th promoter DNA methylation patterns is essential for its continued restriction in postnatal β -cells, and that loss of DNA methylation dysregulates TH expression in β -cells in response to chronic overnutrition, contributing to impairment of β -cell identity. These data highlight the essential requirement of DNA methylation patterning in regulating endocrine cell fates, and reveal a novel role of DNA methylation in β -cell heterogeneity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":303258,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":995858,"name":"Jean Kimi Wang","orcid":null,"position":1,"is_corresponding":false},{"id":434047,"name":"S. Bhattacharya","orcid":"0000-0003-0483-2149","position":2,"is_corresponding":false},{"id":805637,"name":"Janielle Cuala","orcid":"0000-0003-4843-1611","position":3,"is_corresponding":false},{"id":995497,"name":"Mohan Singh Rajkumar","orcid":"0009-0008-0657-4079","position":4,"is_corresponding":false},{"id":108571,"name":"Xiwei Wu","orcid":"0000-0002-7071-1671","position":5,"is_corresponding":false},{"id":323901,"name":"Hung-Ping Shih","orcid":"0000-0003-3035-5841","position":6,"is_corresponding":false},{"id":659770,"name":"Senta Georgia","orcid":"0000-0002-2016-7866","position":7,"is_corresponding":false},{"id":486438,"name":"Sangeeta Dhawan","orcid":"0000-0002-1562-7899","position":8,"is_corresponding":false},{"id":678930,"name":"Nazia Parveen","orcid":"0000-0002-2918-9498","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T00:32:24.307938Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}