Isoform-specific transcriptional activity of overlapping target genes that respond to thyroid hormone receptors alpha1 and beta1

Mol Endocrinol. 2009 Nov;23(11):1758-75. doi: 10.1210/me.2009-0025. Epub 2009 Jul 23.

Abstract

Thyroid hormone receptors (TRs) are hormone-regulated transcription factors that control multiple aspects of physiology and development. TRs are expressed in vertebrates as a series of distinct isoforms that exert distinct biological roles. We wished to determine whether the two most widely expressed isoforms, TR alpha 1 and TR beta 1, exert their different biological effects by regulating different sets of target genes. Using stably transformed HepG2 cells and a microarray analysis, we were able to demonstrate that TR alpha 1 and TR beta 1 regulate a largely overlapping repertoire of target genes in response to T(3) hormone. However, these two isoforms display very different transcriptional properties on each individual target gene, ranging from a much greater T(3)-mediated regulation by TR alpha 1 than by TR beta 1, to near equal regulation by both isoforms. We also identified TR alpha 1 and TR beta 1 target genes that were regulated by these receptors in a hormone-independent fashion. We suggest that it is this gene-specific, isoform-specific amplitude of transcriptional regulation that is the likely basis for the appearance and maintenance of TR alpha 1 and TR beta 1 over evolutionary time. In essence, TR alpha 1 and TR beta 1 adjust the magnitude of the transcriptional response at different target genes to different levels; by altering the ratio of these isoforms in different tissues or at different developmental times, the intensity of T(3) response can be individually tailored to different physiological and developmental requirements.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • Genes, Overlapping
  • Humans
  • Oligonucleotide Array Sequence Analysis
  • Plasmids / metabolism
  • Protein Isoforms
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thyroid Hormone Receptors alpha / chemistry*
  • Thyroid Hormone Receptors alpha / physiology
  • Time Factors
  • Transcription, Genetic
  • Triiodothyronine / chemistry

Substances

  • Protein Isoforms
  • Thyroid Hormone Receptors alpha
  • Triiodothyronine