Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells

TR alpha 1 and TR beta 1, the two main thyroid hormone receptors in mammals, are transcription factors that share similar properties. However, their respective functions are very different. This functional divergence might be explained in two ways: it can reflect different expression patterns or result from different intrinsic properties of the receptors. We tested this second hypothesis by comparing the repertoires of 3,3',5-triiodo-L-thyronine (T3)-responsive genes of two neural cell lines, expressing either TR alpha 1 or TR beta 1. Using transcriptome analysis, we found that a substantial fraction of the T3 target genes display a marked preference for one of the two receptors. So when placed alone in identical situations, the two receptors have different repertoires of target genes. Chromatin occupancy analysis, performed at a genome-wide scale, revealed that TR alpha 1 and TR beta 1 cistromes were also different. However, receptor-selective regulation of T3 target genes did not result from receptor-selective chromatin occupancy of their promoter regions. We conclude that modification of TR alpha 1 and TR beta 1 intrinsic properties contributes in a large part to the divergent evolution of the receptors' function, at least during neurodevelopment.