The Book of Opposites: The Role of the Nuclear Receptor Co-regulators in the Suppression of Epidermal Genes by Retinoic Acid and Thyroid Hormone Receptors

Abstract

Transcriptional regulation by nuclear receptors occurs through complex interactions that involve DNA response elements, co-activators/co-repressors, and histone modifying enzymes. Very little is known about how molecular interplay of these components may determine tissue specificity of hormone action. We have shown previously that retinoic acid (RA) and thyroid hormone (T3) repress transcription of a specific group of epidermal keratin genes through a novel mechanism that utilizes receptors homodimers. In this paper, we have analyzed the epidermal specificity of RA/T3 action by testing the role of co-repressors and co-activators in regulation of epidermal genes. Using transient co-transfections, northern blots, antisense oligonucleotides, and a histone deacetylase (HDAC) inhibitor, trichostatin A, we found that in the context of specific keratin RE (KRE), co-activators and histone acetylase become co-repressors of the RA/T3 receptors in the presence of their respective ligands. Conversely, co-repressors and HDAC become co-activators of unliganded T3Ralpha. The receptor-co-activator interaction is intact and occurs through the NR-box. Therefore, the role of co-activator is to associate with liganded receptors whereas the KRE-receptor interaction determines specific transcriptional signal, in this case repression. This novel molecular mechanism of transcriptional repression conveys how RA and T3 target specific groups of epidermal genes, thus exerting intrinsic tissue specificity.

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

“…Interestingly, the frequency of proximal TRBS is low for genes that are negatively regulated by T3. Therefore, our data do not provide statistical support to the hypothesis that liganded TR can also act as a transcription repressor, as suggested for several genes in other systems (44).…”

Attenuation of the Transforming Growth Factor β-Signaling Pathway in Chronic Venous Ulcers

“…The keratinocytes were grown, without feeder cells, in defined serum-free keratinocyte medium supplemented with epidermal growth factor and bovine pituitary extract (Keratinocyte-SFM; Gibco, Carlsbad, CA, USA) (31,32,39). Cells were expanded through two 1:4 passages and grown to 80% confluence after being washed with 1XPBS several times before incubation in basal keratinocyte medium (Gibco) that was custom made without phenol-red, hydrocortisone and thyroid hormone.…”

Regulation of keratin expression by retinoids

“…51 Clearly, keratin gene expression is affected by retinoids in many complex ways, and it is obvious that classical RARE-activation by RAR/RXR heterodimers is not always involved. 48,[50][51][52][53][54][55] Among the indirect effects associated with the regulation of several keratin genes are interactions with AP-1 and NFκB signaling pathways (see above). Recently it was shown in mouse skin that topical application of the natural compound sulforaphane induced K16 and K17 via AP-1 activation.…”