Comparative analysis of transcriptome profiles reveals distinct and organ-dependent genomic and nongenomic actions of thyroid hormone in Xenopus tropicalis tadpoles.

BACKGROUND Thyroid hormone (T3) is essential for development and organ metabolism in all vertebrates. T3 has both genomic and nongenomic effects on target cells. While much has been learnt on its genomic effects via T3 receptors (TRs) in vertebrate development, mostly through TR-knockout and knockin studies, little is known about the effects of T3 on gene expression in animals in the absence of TR. We have been studying Xenopus metamorphosis as a model for mammalian postembryonic development, a period around birth when plasma T3 level peaks and many organs/tissues mature into their adult forms. We have recently generated TR double knockout (TRDKO) Xenopus tropicalis animals. This offers an opportunity to compare the effects of T3 on global gene expression in tadpole tissues in the presence or absence of TR. METHODS We analyzed the effects of T3 on gene expression in tadpole tail and intestine by using RNA-seq analysis on wild-type and TRDKO tadpoles with or without T3 treatment. RESULTS We observed that removing TRs reduced the number of genes regulated by T3 in both organs. Gene Ontology (GO) and KEGG pathway analyses revealed that T3 affected distinct biological processes and pathways in wild-type and TRDKO tadpoles. Many GO terms and KEGG pathways were enriched among genes regulated in wild-type tissues are likely involved in mediating the effects of T3 on metamorphosis, e.g., those related to development, stem cells, apoptosis, and cell cycle/cell proliferation. However, such GO terms and pathways were not enriched among T3-regulated genes in TRDKO tadpoles. Instead, in TRDKO tadpoles, GO terms and pathways related to "metabolism" and "immune response" were highly enriched among T3-regulated genes. We further observed strong divergence in the TR-independent, nongenomic effects of T3 in the intestine and tail. CONCLUSIONS Our data suggest that T3 have distinct and organ-dependent effects on gene expression in developing tadpoles. The TR-mediated effects are consistent with the metamorphic changes, in agreement with the fact that TR is necessary and sufficient to mediate the effects of T3 on metamorphosis. T3 appears to have a major effect on metabolism and immune response via TR-independent nongenomic processes.

[1]  S. Peng,et al.  Robust induction of B cell and T cell responses by a third dose of inactivated SARS-CoV-2 vaccine , 2021, Cell Discovery.

[2]  M. Dasso,et al.  Thyroid Hormone Receptor Is Essential for Larval Epithelial Apoptosis and Adult Epithelial Stem Cell Development but Not Adult Intestinal Morphogenesis during Xenopus tropicalis Metamorphosis , 2021, Cells.

[3]  C. Beisland,et al.  The epithelial–mesenchymal transition regulators Twist, Slug, and Snail are associated with aggressive tumour features and poor outcome in prostate cancer patients , 2021, The journal of pathology. Clinical research.

[4]  Yunbo Shi.  Life without thyroid hormone receptor. , 2021, Endocrinology.

[5]  Transcriptome profiling reveals gene regulation programs underlying tail development in the Ornamented Pygmy frog Microhyla fissipes , 2021, Frontiers in Bioscience-Landmark.

[6]  Yunbo Shi,et al.  Analysis of thyroid hormone receptor α knockout tadpoles reveals that the activation of cell cycle program. , 2020, Thyroid : official journal of the American Thyroid Association.

[7]  Yunbo Shi,et al.  Thyroid hormone receptor beta is critical for intestinal remodeling during Xenopus tropicalis metamorphosis , 2020, Cell & Bioscience.

[8]  Morihiro Okada,et al.  ORGAN-SPECIFIC REQUIREMENTS FOR THYROID HORMONE RECEPTOR ENSURE TEMPORAL COORDINATION OF TISSUE-SPECIFIC TRANSFORMATIONS AND COMPLETION OF XENOPUS METAMORPHOSIS. , 2019, Thyroid : official journal of the American Thyroid Association.

[9]  D. Gadian,et al.  Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development , 2019, Proceedings of the National Academy of Sciences.

[10]  Yunbo Shi,et al.  Gene Expression Program Underlying Tail Resorption During Thyroid Hormone-Dependent Metamorphosis of the Ornamented Pygmy Frog Microhyla fissipes , 2019, Front. Endocrinol..

[11]  M. Lian,et al.  Survival in Papillary Thyroid Microcarcinoma: A Comparative Analysis Between the 7th and 8th Versions of the AJCC/UICC Staging System Based on the SEER Database , 2019, Front. Endocrinol..

[12]  Y. Yaoita,et al.  Thyroid Hormone Receptor &agr;– and &bgr;–Knockout Xenopus tropicalis Tadpoles Reveal Subtype-Specific Roles During Development , 2018, Endocrinology.

[13]  Jinyoung Choi,et al.  Growth, Development, and Intestinal Remodeling Occurs in the Absence of Thyroid Hormone Receptor &agr; in Tadpoles of Xenopus tropicalis , 2017, Endocrinology.

[14]  Yunbo Shi,et al.  Thyroid Hormone Receptor α Controls Developmental Timing and Regulates the Rate and Coordination of Tissue-Specific Metamorphosis in Xenopus tropicalis , 2017, Endocrinology.

[15]  Yunbo Shi,et al.  Direct Regulation of Histidine Ammonia-Lyase 2 Gene by Thyroid Hormone in the Developing Adult Intestinal Stem Cells , 2017, Endocrinology.

[16]  Y. Kakeji,et al.  Wnt5a‐Ror2 signaling in mesenchymal stem cells promotes proliferation of gastric cancer cells by activating CXCL16–CXCR6 axis , 2016, Cancer science.

[17]  P. Davis,et al.  Nongenomic actions of thyroid hormone , 2016, Nature Reviews Endocrinology.

[18]  D. Angelov,et al.  The thyroid hormone nuclear receptor TRα1 controls the Notch signaling pathway and cell fate in murine intestine , 2015, Development.

[19]  R. Bazinet,et al.  Is docosahexaenoic acid synthesis from α-linolenic acid sufficient to supply the adult brain? , 2015, Progress in lipid research.

[20]  P. Davis,et al.  Overlapping nongenomic and genomic actions of thyroid hormone and steroids , 2015, Best practice & research. Clinical endocrinology & metabolism.

[21]  Yunbo Shi,et al.  A requirement for hedgehog signaling in thyroid hormone-induced postembryonic intestinal remodeling , 2015, Cell & Bioscience.

[22]  Yunbo Shi,et al.  Unliganded thyroid hormone receptor α controls developmental timing in Xenopus tropicalis. , 2015, Endocrinology.

[23]  Julien Nadjar,et al.  The secreted Frizzled-Related Protein 2 modulates cell fate and the Wnt pathway in the murine intestinal epithelium. , 2015, Experimental cell research.

[24]  S. Singh,et al.  The thyroxine inactivating gene, type III deiodinase, suppresses multiple signaling centers in Dictyostelium discoideum. , 2014, Developmental biology.

[25]  G. Brent,et al.  Thyroid hormone regulation of metabolism. , 2014, Physiological reviews.

[26]  E. Kress,et al.  Thyroid hormones and their nuclear receptors: new players in intestinal epithelium stem cell biology? , 2014, Cellular and Molecular Life Sciences.

[27]  F. B. Davis,et al.  Nongenomic effects of thyroid hormones on the immune system cells: New targets, old players , 2012, Steroids.

[28]  J. Massagué,et al.  TGF‐β control of stem cell differentiation genes , 2012, FEBS letters.

[29]  R. Farías,et al.  Cooperative nongenomic and genomic actions on thyroid hormone mediated‐modulation of T cell proliferation involve up‐regulation of thyroid hormone receptor and inducible nitric oxide synthase expression , 2011, Journal of cellular physiology.

[30]  P. Davis,et al.  Molecular aspects of thyroid hormone actions. , 2010, Endocrine reviews.

[31]  Yunbo Shi.  Dual functions of thyroid hormone receptors in vertebrate development: the roles of histone-modifying cofactor complexes. , 2009, Thyroid : official journal of the American Thyroid Association.

[32]  S. Hedrick.  The cunning little vixen: Foxo and the cycle of life and death , 2009, Nature Immunology.

[33]  J. Cidlowski,et al.  Apoptosis and glutathione: beyond an antioxidant , 2009, Cell Death and Differentiation.

[34]  B. Olsen,et al.  Snail and Slug promote epithelial-mesenchymal transition through beta-catenin-T-cell factor-4-dependent expression of transforming growth factor-beta3. , 2008, Molecular biology of the cell.

[35]  H. Matsuda,et al.  Developmental regulation and function of thyroid hormone receptors and 9-cis retinoic acid receptors during Xenopus tropicalis metamorphosis. , 2008, Endocrinology.

[36]  Yunbo Shi,et al.  Thyroid hormone–up‐regulated hedgehog interacting protein is involved in larval‐to‐adult intestinal remodeling by regulating sonic hedgehog signaling pathway in Xenopus laevis , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[37]  S. Peng,et al.  Foxo in the immune system , 2008, Oncogene.

[38]  Thomas S. Scanlan,et al.  Rapid nongenomic actions of thyroid hormone , 2006, Proceedings of the National Academy of Sciences.

[39]  N. Marsh-Armstrong,et al.  Thyroid hormone controls multiple independent programs required for limb development in Xenopus laevis metamorphosis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[40]  P. Meltzer,et al.  Effects of ligand and thyroid hormone receptor isoforms on hepatic gene expression profiles of thyroid hormone receptor knockout mice , 2003, EMBO reports.

[41]  Duo Li,et al.  What is the role of α-linolenic acid for mammals? , 2002, Lipids.

[42]  F. B. Davis,et al.  Nongenomic actions of thyroid hormone on the heart. , 2002, Thyroid : official journal of the American Thyroid Association.

[43]  Yunbo Shi,et al.  Thyroid hormone regulation of apoptotic tissue remodeling during anuran metamorphosis , 2001, Cell Research.

[44]  N. Marsh-Armstrong,et al.  Diverse developmental programs of Xenopus laevis metamorphosis are inhibited by a dominant negative thyroid hormone receptor , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[45]  T. Takeuchi,et al.  Effect of Thyroid Hormones on the Stage-specific Pigmentation of the Japanese Flounder Paralichthys olivaceus , 2000, Zoological science.

[46]  D. Forrest,et al.  Functions of thyroid hormone receptors in mice. , 2000, Thyroid : official journal of the American Thyroid Association.

[47]  F. B. Davis,et al.  Nongenomic actions of thyroid hormone. , 1996, Thyroid : official journal of the American Thyroid Association.