title: Gene specific actions of thyroid hormone receptor subtypes.
abstract: There are two homologous thyroid hormone (TH) receptors (TRs α and β), which are members of the nuclear hormone receptor (NR) family. While TRs regulate different processes in vivo and other highly related NRs regulate distinct gene sets, initial studies of TR action revealed near complete overlaps in their actions at the level of individual genes. Here, we assessed the extent that TRα and TRβ differ in target gene regulation by comparing effects of equal levels of stably expressed exogenous TRs +/- T(3) in two cell backgrounds (HepG2 and HeLa). We find that hundreds of genes respond to T(3) or to unliganded TRs in both cell types, but were not able to detect verifiable examples of completely TR subtype-specific gene regulation. TR actions are, however, far from identical and we detect TR subtype-specific effects on global T(3) response kinetics in HepG2 cells and many examples of TR subtype specificity at the level of individual genes, including effects on magnitude of response to TR +/- T(3), TR regulation patterns and T(3) dose response. Cycloheximide (CHX) treatment confirms that at least some differential effects involve verifiable direct TR target genes. TR subtype/gene-specific effects emerge in the context of widespread variation in target gene response and we suggest that gene-selective effects on mechanism of TR action highlight differences in TR subtype function that emerge in the environment of specific genes. We propose that differential TR actions could influence physiologic and pharmacologic responses to THs and selective TR modulators (STRMs).
authors.affiliation: Genomic Medicine, The Methodist Hospital Research Institute, Houston, Texas, United States of America.
authors.forename: Jean Z
authors.initials: JZ
authors.lastname: Lin
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Sieglaff
authors.forename: Chaoshen
authors.initials: C
authors.lastname: Yuan
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.forename: Anithachristy S
authors.initials: AS
authors.lastname: Arumanayagam
authors.forename: Sharareh
authors.initials: S
authors.lastname: Firouzbakht
authors.forename: Jaime J
authors.initials: JJ
authors.lastname: Cantu Pompa
authors.forename: Frances Denoto
authors.initials: FD
authors.lastname: Reynolds
authors.forename: Xiabo
authors.initials: X
authors.lastname: Zhou
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Cvoro
authors.forename: Paul
authors.initials: P
authors.lastname: Webb
mesh_terms: D003513:Cycloheximide / Q000494:pharmacology*; D018076:DNA, Complementary / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics* / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000235:genetics* / Q000378:metabolism; D014284:Triiodothyronine / Q000494:pharmacology
chemical_list: D018076:DNA, Complementary; D037021:Thyroid Hormone Receptors alpha; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D003513:Cycloheximide