Isoform-specific transcriptional activity of overlapping targets that respond to thyroid hormone receptors a1 and b1

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 if the two most widely expressed isoforms, TRa1 and TRb1, 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 TRa1 and TRb1 regulate a largely overlapping repertoire of target genes in response to T3 hormone. However, these two isoforms display very different transcriptional properties on each individual target gene, ranging from a much greater T3-mediated regulation by TRa1 than by TRb1, to near equal regulation by both isoforms. We also identified TRa1 and TRb1 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 TRa1 and TRb1 over evolutionary time. In essence, TRa1 and TRb1 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 T3 response can be individually tailored to different physiological and developmental requirements.

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Chan IH, Privalsky ML