title: Ligand Independent and Subtype-Selective Actions of Thyroid Hormone Receptors in Human Adipose Derived Stem Cells.
abstract: Thyroid hormone (TH) receptors (TRs α and β) are homologous ligand-dependent transcription factors (TFs). While the TRs display distinct actions in development, metabolic regulation and other processes, comparisons of TRα and TRβ dependent gene regulation mostly reveal similar mechanisms of action and few TR subtype specific genes. Here, we show that TRα predominates in multipotent human adipose derived stem cells (hADSC) whereas TRβ is expressed at lower levels and is upregulated during hADSC differentiation. The TRs display several unusual properties in parental hADSC. First, TRs display predominantly cytoplasmic intracellular distribution and major TRα variants TRα1 and TRα2 colocalize with mitochondria. Second, knockdown experiments reveal that endogenous TRs influence hADSC cell morphology and expression of hundreds of genes in the absence of hormone, but do not respond to exogenous TH. Third, TRα and TRβ affect hADSC in completely distinct ways; TRα regulates cell cycle associated processes while TRβ may repress aspects of differentiation. TRα splice variant specific knockdown reveals that TRα1 and TRα2 both contribute to TRα-dependent gene expression in a gene specific manner. We propose that TRs work in a non-canonical and hormone independent manner in hADSC and that prominent subtype-specific activities emerge in the context of these unusual actions.
authors.affiliation: Genomic Medicine, Houston Methodist Research Institute, Houston, TX, United States of America.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Cvoro
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States of America.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, United States of America.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Bajic
authors.affiliation: Genomic Medicine, Houston Methodist Research Institute, Houston, TX, United States of America.
authors.forename: Aijun
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Genomic Medicine, Houston Methodist Research Institute, Houston, TX, United States of America.
authors.forename: Marisa
authors.initials: M
authors.lastname: Simon
authors.affiliation: University of Belgrade - Faculty of Biology, 11000, Belgrade, Serbia.
authors.forename: Igor
authors.initials: I
authors.lastname: Golic
authors.affiliation: Genomic Medicine, Houston Methodist Research Institute, Houston, TX, United States of America.
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Sieglaff
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States of America.|Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, United States of America.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Maletic-Savatic
authors.affiliation: University of Belgrade - Faculty of Biology, 11000, Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Korac
authors.affiliation: Genomic Medicine, Houston Methodist Research Institute, Houston, TX, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006801:Humans; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000032:analysis / Q000235:genetics / Q000378:metabolism
chemical_list: D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine