Ligand Independent and Subtype-Selective Actions of Thyroid Hormone Receptors in Human Adipose Derived Stem Cells.

ABSTRACT: Thyroid hormone (TH) receptors (TRs ? and ?) are homologous ligand-dependent transcription factors (TFs). While the TRs display distinct actions in development, metabolic regulation and other processes, comparisons of TR? and TR? dependent gene regulation mostly reveal similar mechanisms of action and few TR subtype specific genes. Here, we show that TR? predominates in multipotent human adipose derived stem cells (hADSC) whereas TR? 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 TR? variants TR?1 and TR?2 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, TR? and TR? affect hADSC in completely distinct ways; TR? regulates cell cycle associated processes while TR? may repress aspects of differentiation. TR? splice variant specific knockdown reveals that TR?1 and TR?2 both contribute to TR?-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.

SUBMITTER: Cvoro A 

PROVIDER: S-EPMC5061422 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature