TY - JOUR
T1 - Ligand independent and subtype-selective actions of thyroid hormone receptors in human adipose derived stem cells
AU - Cvoro, Aleksandra
AU - Bajic, Aleksandar
AU - Zhang, Aijun
AU - Simon, Marisa
AU - Golic, Igor
AU - Sieglaff, Douglas H.
AU - Maletic-Savatic, Mirjana
AU - Korac, Aleksandra
AU - Webb, Paul
N1 - Funding Information:
This work was supported by NIH UO1 GM094614 subcontract to PW. Confocal microscopy was done in IDDRC Microscopy Core and supported by IDDRC grant 1U54 HD083092 from Eunice Kennedy Shriver NICHD and Center for Electron Microscopy at Faculty of Biology, University of Belgrade. Flow cytometry was done by the Cytometry and Cell Sorting Core at Baylor College of Medicine with NIH funding (P30 AI036211, P30 CA125123, and S10 RR024574) and expert assistance of Joel M. Sederstrom.
Publisher Copyright:
© 2016 Cvoro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/10
Y1 - 2016/10
N2 - Thyroid hormone (TH) receptors (TRs α and β) are homologous ligand-dependent transcriptio factors (TFs). While the TRs display distinct actions in development, metaboli regulation and other processes, comparisons of TRα and TRβ dependent gene regulatio mostly reveal similar mechanisms of action and few TR subtype specific genes. Here, w 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 predominantl cytoplasmic intracellular distribution and major TRα variants TRα1 and TRα2 colocaliz with mitochondria. Second, knockdown experiments reveal that endogenous TR influence hADSC cell morphology and expression of hundreds of genes in the absence o hormone, but do not respond to exogenous TH. Third, TRα and TRβ affect hADSC i completely distinct ways; TRα regulates cell cycle associated processes while TRβ ma repress aspects of differentiation. TRα splice variant specific knockdown reveals that TRα 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 i hADSC and that prominent subtype-specific activities emerge in the context of thes unusual actions.
AB - Thyroid hormone (TH) receptors (TRs α and β) are homologous ligand-dependent transcriptio factors (TFs). While the TRs display distinct actions in development, metaboli regulation and other processes, comparisons of TRα and TRβ dependent gene regulatio mostly reveal similar mechanisms of action and few TR subtype specific genes. Here, w 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 predominantl cytoplasmic intracellular distribution and major TRα variants TRα1 and TRα2 colocaliz with mitochondria. Second, knockdown experiments reveal that endogenous TR influence hADSC cell morphology and expression of hundreds of genes in the absence o hormone, but do not respond to exogenous TH. Third, TRα and TRβ affect hADSC i completely distinct ways; TRα regulates cell cycle associated processes while TRβ ma repress aspects of differentiation. TRα splice variant specific knockdown reveals that TRα 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 i hADSC and that prominent subtype-specific activities emerge in the context of thes unusual actions.
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U2 - 10.1371/journal.pone.0164407
DO - 10.1371/journal.pone.0164407
M3 - Article
C2 - 27732649
AN - SCOPUS:84991511087
VL - 11
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 10
M1 - e0164407
ER -