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Non-canonical thyroid hormone signaling mediates cardiometabolic effects in vivo

ABSTRACT: Non-canonical thyroid hormone signaling mediates cardiometabolic effects in vivo

OTHER RELATED OMICS DATASETS IN: GSE93864

PROVIDER: PRJNA414077 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6163880.fastq.gz	Fastqsanger.gz
	SRR6163881.fastq.gz	Fastqsanger.gz
	SRR6163882.fastq.gz	Fastqsanger.gz
	SRR6163873.fastq.gz	Fastqsanger.gz
	SRR6163883.fastq.gz	Fastqsanger.gz

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Similar Datasets

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.

2017-11-01 | GSE104877 | GEO

A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in liver

Project description:Thyroid hormones (TH) are powerful regulators of metabolism with major effects on body weight, cholesterol, and liver fat that have been exploited pharmacologically for many years. Activation of gene expression by TH action is canonically ascribed to a hormone- dependent “switch” from corepressor to activator binding to thyroid hormone receptors (TR), while the mechanism of TH-dependent repression is controversial. To address this, we generated a mouse line in which endogenous TRβ1 was epitope-tagged to allow precise chromatin immunoprecipitation at the low physiological levels of TR, and defined high confidence binding sites where TR functioned at enhancers regulated in the same direction as the nearest gene in a TRβ-dependent manner. Remarkably, although positive and negative regulation by TH have been ascribed to different mechanisms, TR binding was highly enriched at canonical DR4 motifs irrespective of the transcriptional direction of the enhancer. The canonical NCoR1/HDAC3 corepressor complex was reduced but not completely dismissed by TH and, surprisingly, similar effects were seen at enhancers associated with negatively as well as positively regulated genes. Conversely, coactivator CBP was found at all TH-regulated enhancers, with transcriptional activity correlating with the ratio of CBP to NCoR rather than their presence or absence. These results demonstrate that, in contrast to the canonical “all or none” coregulator switch model, TH regulates gene expression by orchestrating a shift in the relative binding of corepressors and coactivators.

2021-01-01 | GSE159648 | GEO

Thyroid hormone receptor beta is required for thyrotrpin regulation and thyroid hormone production.

Project description:Thyroid hormone receptor beta is required for thyrotrpin regulation and thyroid hormone production.

| PRJNA703005 | ENA

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

Project description:Using tadpoles mutant for thyroid hormone receptor alpha (thra), we show that TRa is required for thyroid hormone (T3) induction of cell proliferation in the brain. RNA-sequencing showed that the TRa is required for 95% of the gene regulation responses to T3.

2019-05-13 | GSE130816 | GEO

Thyroid hormone receptor a in skeletal muscle is essential for thyroid thermogenesis

Project description:Thyroid hormones are important for homeostatic control of energy metabolism and body temperature. Although skeletal muscle is considered an important site for thyroid action, the contribution of thyroid hormone receptor signaling, in muscle, to whole-body energy metabolism and body temperature has not been resolved. Here, we show that thyroid hormone-induced increase in energy expenditure requires thyroid hormone receptor alpha 1 (TRa1) in skeletal muscle, but that thyroid hormone induced elevation in body temperature is independent of muscle-TRa1. In slow-twitch soleus muscle, ablation of TRa1 leads to an altered fiber type composition toward a more oxidative phenotype, which, however, does not influence running capacity or motivation to voluntary running. RNA-sequencing of soleus muscle from WT mice and TRaHSACre mice revealed differentiated transcriptional regulation of genes associated with muscle thermogenesis, such as sarcolipin and UCP3, thus providing molecular clues pertaining to the mechanistic underpinnings of TRa1-linked control of whole-body metabolic rate. Together, this work establishes a fundamental role for skeletal muscle in thyroid hormone-stimulated increase in whole-body energy expenditure.

2020-09-21 | GSE146336 | GEO

A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in liver

Project description:A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in liver

| PRJNA669898 | ENA

Target genes of thyroid hormone in cerebellum neurons

2012-03-30 | GSE24793 | GEO

A cardiac developmental defect prevents thyroid hormone induced tachycardia in Resistance to Thyroid Hormone alpha

Project description:A cardiac developmental defect prevents thyroid hormone induced tachycardia in Resistance to Thyroid Hormone alpha

| PRJNA850193 | ENA

Target genes of thyroid hormone in cerebellum neurons

Project description:Cerebellar post-natal development is particularly sensitive to thyroid hormone and low levels of thyroid hormone (hypothyroidism) result in permanent defects in cerebellar architecture and function. All cell types of the cerebellum are affected, but the main sign of hypothyroidism in mice is the persistence of the external granular layer, composed of mitotic neuronal precursors at P21. To make the genetic link between thyroid hormone and cerebellar development, we sought to identify new thyroid hormone target genes, in particular in granule cells which represent the vast majority of cerebellar cells. Primary cultures of cerebellar neurons were made by dissociation of cerebella from newborn wild-type mice. These cells were plated 48 hours in serum-free medium to avoid invasion of the culture by glial cells. In order to include a kinetic and a maximum number of target genes, several cultures were either treated or left untreated as controls for 6 hours (T1), 16 hours (T2), 24 hours (T3) or 48 hours (T4) and results were pairwise compared for each time point.

2012-03-29 | E-GEOD-24793 | biostudies-arrayexpress

Generation of thyroid follicular cell organoids from adult thyroid tissue [mouse]

Project description:The thyroid maintains systemic homeostasis by regulating serum thyroid hormone concentrations. Here we report the establishment of adult stem cell-derived three-dimensional (3D) organoids representing murine and human thyroid follicular cells (TFCs). The TFC organoids (TFCO) harbour the complete machinery of hormone production as visualised by the presence of colloid in the lumen and by the presence of essential transporters and enzymes in the polarised epithelial cells that surround a central lumen. Both the established murine as human thyroid organoids express canonical thyroid markers PAX8 and NKX2.1, while the thyroid hormone precursor thyroglobulin is expressed at comparable levels to tissue. Single cell RNA sequencing and transmission electron microscopy confirm that TFCOs phenocopy primary thyroid tissue. Thyroid hormones are readily detectable in conditioned medium of human TFCOs.

2021-12-06 | GSE183962 | GEO

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