{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE331nnn/GSE331533/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Genomics"],"species":["Homo sapiens"],"gds_type":["Genome binding/occupancy profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE331533"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"CDK8 regulates definitive endoderm commitment through cAMP-lysosomal homeostasis and neuroectodermal suppression [CUT&Tag]","description":"Definitive endoderm (DE) specification is critical for generating gastrointestinal and respiratory organs, yet upstream molecular checkpoints integrating transcriptional control with metabolic regulation remain incompletely defined. Here, we identify cyclin-dependent kinase 8 (CDK8) as a decisive regulator of human DE commitment. Profiling CDK8 expression during pluripotent stem cell differentiation revealed stage-specific upregulation, while pharmacological inhibition or genetic ablation of CDK8 severely compromised DE formation and hepatic competency. Mechanistically, CDK8 directly represses neuroectoderm programs while concurrently activating endoderm-lysosomal transcriptional networks. CDK8 deficiency triggered convergent dysregulation of EPAC-dependent cAMP signaling hyperactivation and lysosomal dysfunction, underpinning the DE defect. Integrative multi-omics (RNA-seq, CUT&Tag) demonstrated that CDK8 licenses lineage commitment by directly suppressing neural differentiation genes and enhancing endoderm-TGFβ pathways through recruitment to promoter-proximal regulatory elements. Our work establishes the CDK8 as a metabolic-epigenetic checkpoint for endoderm specification, offering novel mechanistic insights into cell fate determination and therapeutic strategies for developmental disorders of endoderm-derived organs.","dates":{"publication":"2026/09/14"},"accession":"GSE331533","cross_references":{"GSM":["GSM9749299","GSM9749300","GSM9749298","GSM9749301","GSM9749302"],"GPL":["24676"],"GSE":["331533"],"taxon":["Homo sapiens"]}}