Thyroid hormone-mediated negative transcriptional regulation of Necdin expression

Abstract

Unliganded thyroid hormone receptors (apoTRs) repress transcription of hormone-activated genes by recruiting corepressors to the promoters. In contrast, on promoters containing so-called negative thyroid hormone response elements (nTREs), apoTRs activate transcription. A number of different molecular mechanisms have been described as to how apoTRs activate transcription varying with the target gene of the study. Here we demonstrate that thyroid hormone regulates the transcription of the Necdin gene, a developmentally regulated candidate gene for the genomic imprinting-associated neurobehavioural disorder, Prader-Willi syndrome. ApoTRs activate Necdin expression through an nTRE in its promoter, downstream of the transcription start site. The nTRE of the Necdin gene resembles the nTREs of the TSH genes of the hypothalamus-pituitary-thyroid axis in the sequence, position in the promoter, and mode of activation. We show that this group of nTRE-driven genes shares the requirements for binding of the retinoic X receptor and nuclear receptor corepressor/silencing mediator of retinoid and thyroid hormone receptors (NCoR/SMRT) for full ligand-independent activation, whereas there is no need for association of the p160 family of coactivators. In accordance with the requirement for corepressors, Necdin expression is influenced by deacetylase activity, suggesting that histone deacetylases and corepressors as well could function as activators of transcription, depending on the promoter context.

A combined approach identifies a limited number of new thyroid hormone target genes in post-natal mouse cerebellum

“…This reinforces the view that the current model for TR-mediated transcription Thyroid hormone target genes in cerebellum . L QUIGNODON and others 25 (Rosenfeld et al 2006) is still incomplete (Nygard et al 2003(Nygard et al , 2006. The expression of Akap1, Kirrel3, Lrrn1, and Tgm1 was not significantly reduced in hypothyroid Pax8 K/K mice when compared with wild type.…”

Necdin Controls Foxo1 Acetylation in Hypothalamic Arcuate Neurons to Modulate the Thyroid Axis

“…These responses may be attributed to the T3-induced Ndn suppression in the ARC. Because Ndn transcription is negatively regulated by T3 (Nygård et al, 2006), it is possible that T3 directly suppresses hypothalamic Ndn expression. However, acute T3 administration reduced the necdin protein level (Fig.…”

The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription

“…Positive regulation of mGPDH is accomplished by a welldescribed TRE that is located close to the transcriptional start site (Weitzel et al 2001b). Another DNA-binding motif in close vicinity to the transcriptional start site (the so-called z-box) is believed to be responsible for TR binding and negative regulation of the TSHb and necdin genes (Sasaki et al 1999, Nygard et al 2006. However, we could not detect any direct TR-DNA binding to the TSHa promoter in our cell-based assay (Fig.…”

“…Furthermore, TR binds extremely weakly to 'negative' TREs compared with classical 'positive' TREs in electrophoretic mobility shift assays (Sasaki et al 1999, Kim et al 2005, Hashimoto et al 2006. Interestingly, most of the suggested binding sites for TR are located close to the transcriptional start site within negatively regulated genes (Sasaki et al 1999, Villa et al 2004, Furumoto et al 2005, Kim et al 2005, Hashimoto et al 2006, Nygard et al 2006, Santos et al 2006. It remains to be elucidated whether alterations at the transcriptional start site influence the composition of the transcription machinery accounting for the observed negative regulation of gene expression by T 3 .…”

“…Thus, the functional readout on a negative TRE is diametrically opposed to the readout on a positive TRE. DNA sequences close to the transcriptional start site (the so-called z-boxes) have been suggested to be the binding sites for TR within the TRH, thyroid-stimulating hormone b (TSHb), and necdin gene promoters (Sasaki et al 1999, Satoh et al 1999, Shibusawa et al 2003a, Nygard et al 2006. In a second model, TR inhibits the function of another DNA-binding protein in a liganddependent manner.…”