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CDK8 regulates definitive endoderm commitment through cAMP-lysosomal homeostasis and neuroectodermal suppression [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306078 | GEO | 2026/09/14

REPOSITORIES: GEO

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CDK8 regulates definitive endoderm commitment through cAMP-lysosomal homeostasis and neuroectodermal suppression [CUT&Tag]

Project 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.

2026-09-14 | GSE306077 | GEO

CDK8 regulates definitive endoderm commitment through cAMP-lysosomal homeostasis and neuroectodermal suppression [CUT&Tag]

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CDK8 regulates definitive endoderm commitment through cAMP-lysosomal homeostasis and neuroectodermal suppression [CUT&Tag]

Project description:CDK8 regulates definitive endoderm commitment through cAMP-lysosomal homeostasis and neuroectodermal suppression [CUT&Tag]

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CDK8 regulates definitive endoderm commitment through cAMP-lysosomal homeostasis and neuroectodermal suppression [CUT&Tag]

Project description:CDK8 regulates definitive endoderm commitment through cAMP-lysosomal homeostasis and neuroectodermal suppression [CUT&Tag]

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CDK8 regulates definitive endoderm commitment through cAMP-lysosomal homeostasis and neuroectodermal suppression [RNA-seq]

Project description:CDK8 regulates definitive endoderm commitment through cAMP-lysosomal homeostasis and neuroectodermal suppression [RNA-seq]

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Human organoids uncover PTEN-driven mesendoderm specification via inhibition of retinoic acid signaling pathways

Project description:Epiblast cells ingress into the primitive streak, undergoing mesendoderm (MES) specification, which subsequently gives rise to the mesoderm and endoderm. Although recent advances in human organoid technology facilitating the study of early post-implantation development, robust human models that accurately recapitulate MES specification and primitive streak (PS) formation remain lacking. Here, we showed that human induced pluripotent stem cells (iPSCs) can be employed to generate three-dimensional (3D) MES organoids that closely mimic in vivo human MES specification, particularly the cells from the anterior region of primitive streak. We revealed that formation of MES organoids depended on the appearance of PTEN, and PTEN abrogation potently impaired the MES organoids-derived definitive endoderm and mesoderm specification. To elucidate the molecular mechanisms underlying the defects induced by PTEN loss, we performed integrative multi-omic analyses‒including RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), and phospho‒proteomics‒on WT and PTEN−/− MES cells. These analyses indicated retinoic acid (RA) signalling as a critical pathway suppressed by PTEN during MES lineage specification. Moreover, we identified CYP26A1, a RA-degrading enzyme, as a key downstream effector of PTEN in MES cell generation. Notably, our results demonstrated that excessive RA was detrimental, while an optimal level of RA was indispensable for MES cell generation. Overall, our MES organoids provide a valuable platform for investigating human MES specification, and our findings demonstrated PTEN as a driver of MES lineage commitment through the inhibition of RA signalling.

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Parallel Regulation of Tissue Morphogenesis and Cell Fate Specification by RAR:RXR during Pancreas Formation

Project description:During embryogenesis, morphologically diverse epithelial organs bud out from different regions of the embryonic gut. The unique features of each nascent organ result from distinct cell fate specification and morphogenetic events elicited by organ-inducing cues. Retinoic acid is a powerful inducer of the pancreas, yet, how it regulates pancreas specification and budding from the foregut endoderm remains poorly understood. By modeling these processes using a new hESC organoid system, we demonstrate that both pancreas budding and specification are induced by retinoic acid-mediated transient β-CATENIN depletion. While the reduction of β-CATENIN at the cell membrane weakens cell-cell adhesion, resulting in perturbed apical-basal cell polarity and gut epithelium multi-layering, depletion of the nuclear pool relieves β-CATENIN-mediated repression of FOXA2-dependent Pdx1 transcriptional activation. Our findings provide a new paradigm for how developmental cues coordinate both morphogenetic and cell specification events by targeting proteins with dual roles in cell-cell adhesion and transcription, such as β-CATENIN.

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Dynamic developmental signaling logic underlying lineage bifurcations during human endoderm induction and patterning from pluripotent stem cells [Expression data set]

Project description:The definitive endoderm germ layer is the provenance of multiple internal organs, including the lungs, liver, pancreas and intestines. Molecular events driving initial endoderm germ layer specification and subsequent anterior-posterior patterning of endoderm into distinct organ primordia remain largely cryptic. Through microarray analyses, we captured genome-wide transcriptional dynamics driving successive stages of endoderm development with the intent of identifying novel regulatory genes or diagnostic markers that respectively drive or mark endoderm committment.

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The SETD7–H3K4me1–APLNR Axis Couples Epigenetic Signaling to Orchestrate Endoderm Specification in Human Pluripotent Stem Cells

Project description:The differentiation of human pluripotent stem cells into definitive endoderm (DE), a pivotal event in embryonic development, remains incompletely elucidated with respect to its epigenetic control. Here, we identified SETD7, a histone H3K4 monomethyltransferase (H3K4me1), as dynamically upregulated during DE specification, with its expression correlating strongly with the key lineage marker SOX17. Genetic knockdown of SETD7 impaired DE formation, as evidenced by reduced expression of DE markers and disruption of APLNR-mediated PI3K/AKT/mTOR signaling—a phenotypic defect recapitulated by pharmacological inhibition of APLNR. Mechanistically, SETD7 facilitates H3K4me1 deposition at enhancer regions of APLNR, thereby promoting its transcriptional activation. Our findings unveil an epigenetic-regulatory axis wherein SETD7-mediated enhancer priming drives APLNR expression, ultimately activating the PI3K/AKT/mTOR cascade to promote endodermal commitment. Through an integrated approach incorporating doxycycline-inducible SETD7 knockdown in hESCs, pathway-specific pharmacology, ChIP-qPCR, and 3D organoid modeling, we decipher the spatiotemporal regulatory network governed by SETD7 during DE specification. This study highlights the critical crosstalk between histone modification landscapes and signal transduction during cell fate determination and establishes a novel strategy for manipulating differentiation trajectories.

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microRNA Profiling during endoderm differentiation from mouse embryonic stem cells

Project description:The role of microRNAs (miRNAs) during mouse early development, especially in endoderm germ layer formation, is largely unknown. Here, using miRNA profiling, we discovered that miR-124a negatively regulates endoderm lineage commitment in mouse embryonic stem cells (mESCs). We showed that miR-124a inhibits endoderm differentiation in vitro through targeting the 3’ untranslated region (UTR) of Sox17 and Gata6, revealing the existence of an interplay between miR-124a and Sox17/Gata6 transcription factors in hepato-specific gene regulation. Besides, we proposed an in vivo system that utilizes teratoma to evaluate the functional role of miRNA in lineage specification. We demonstrated that ectopic expression of miR-124a in teratomas suppressed endoderm and mesoderm lineage differentiation while augmented the differentiation of ectoderm lineage. Collectively, our findings suggested that miR-124a plays a significant role in mESCs lineage commitment.

2019-12-31 | GSE131337 | GEO

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