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Thyroid hormone receptor α controls larval intestinal epithelial cell death by regulating the CDK1 pathway

ABSTRACT: Our study represents the first detailed analysis of thyroid hormone binding to the genome in the intestine of wild-type and TRα (-/-) tadpoles, with biological replicates, generated by ChIP-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of TR binding profiles.

ORGANISM(S): Xenopus tropicalis

PROVIDER: GSE161718 | GEO | 2022/07/19

REPOSITORIES: GEO

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ChIP sequencing of wild-type and TRα (-/-) hindlimb with and without T3 Treatment

Project description:Our study represents the first detailed analysis of thyroid hormone binding to the genome in the hindlimb of wild-type and TRα (-/-) tadpoles, with biological replicates, generated by ChIP-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of TR binding profiles.

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Non-canonical thyroid hormone signaling mediates cardiometabolic effects in vivo

Project description:Thyroid hormone (TH) and TH receptors (TRs) α and β act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical pathway for TH action. In addition, however, TRs can activate intra-cellular second messenger signaling pathways. Whether such non-canonical TR signaling is physiologically relevant in vivo is unknown. Here we generated knock-in mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and TREs and leads to a complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite disrupted DNA-binding, most notably heart rate, body temperature, blood glucose and triglyceride concentration, all of which were regulated by non-canonical TR signaling. Additionally, we confirm that TRE-binding defective TRβ leads to disruption of the hypothalamic-pituitary-thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, showing TRE-mediated and tissue-specific canonical signaling. Our findings provide first in vivo evidence that non-canonical TR signaling exerts important cardiometabolic effects, which are clearly separated from canonical actions. Consequently, these data challenge the current paradigm that TH action is exclusively mediated through regulation of gene transcription at the nuclear level.

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Thyroid hormone receptor α controls larval intestinal epithelial cell death by regulating the CDK1 pathway.

Project description:Thyroid hormone (T3) regulates adult intestine development through T3 receptors (TRs). It is difficult to study TR function during postembryonic intestinal maturation in mammals due to maternal influence. We chose intestinal remodeling during Xenopus tropicalis metamorphosis as a model to study TR function in adult organ development. By using ChIP (chromatin immunoprecipitation)-Seq, we identified over 3000 TR-bound genes in the intestine of premetamorphic wild type or TRα (the major TR expressed during premetamorphosis)-knockout tadpoles. Surprisingly, cell cycle-related GO (gene ontology) terms and biological pathways were highly enriched among TR target genes even though the first major event during intestinal metamorphosis is larval epithelial cell death, and TRα knockout drastically reduced this enrichment. More importantly, treatment of tadpoles with cell cycle inhibitors blocked T3-induced intestinal remodeling, especially larval epithelial cell death, suggesting that TRα-dependent activation of cell cycle is important for T3-induced apoptosis during intestinal remodeling.

| S-EPMC8821549 | biostudies-literature

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Project description:Conclusions: Our study represents the first detailed analysis of intestinal transcriptomes in wild-type and TRα (-/-) tadpoles, with biologic replicates, generated by RNA-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles.

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Comparative analysis of transcriptome profiles reveals organ-dependent (Intestine and Tail) genomic and nongenomic actions of thyroid hormone in Xenopus tropicalis tadpoles

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Thyroid hormone receptor alpha is required for thyroid hormone-dependent neural cell proliferation during tadpole metamorphosis

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