Thyroglobulin regulates follicular function and heterogeneity by suppressing thyroid-specific gene expression

Thyroglobulin (TG) is the primary synthetic product of the thyroid and the macromolecular precursor of thyroid hormones. TG synthesis, iodination, sto rage in follicles, and lysosomal degradation can each modulate thyroid horm one formation and secretion into the circulation. Thyrotropin (TSH), via it s receptor (the TSHR), increases thyroid hormone levels by upregulating exp ression of the sodium iodide symporter (NIS), thyroid peroxidase (TPO), and TG genes. TSH does this by modulating the expression and activity of the t hyroid-specific transcription factors, thyroid transcription factor (TTF)-1 , TTF-2, and Pax-8, which coordinately regulate NIS, TPO, TG, and the TSHR. Major histocompatibility complex (MHC) class I gene expression, which is a lso regulated by TTF-1 and Pax-8 in the thyroid, is simultaneously decrease d; this maintains self tolerance in the face of TSH-increased gene products necessary for thyroid hormone formation. We now show that follicular TG, 2 7S > 19S > 12S, counter-regulates TSH-increased thyroid-specific gene trans cription by suppressing the expression of the TTF-1, TTF-2, and Pax-8 genes . This decreases expression of the TG, TPO, NIS and TSHR genes, but increas es class I expression. TG action involves an apical membrane TG-binding pro tein; however, it acts transcriptionally, targeting, for example, a sequenc e within 1.15 kb of the start of TTF-1 transcription. TG does not affect ub iquitous transcription factors regulating TG, TPO, MS and/or TSHR gene expr ession. TG activity is not duplicated by thyroid hormones or iodide. We hyp othesize that TG-initiated, transcriptional regulation of thyroid-restricte d genes is a normal, feedback, compensatory mechanism which regulates folli cular function, regulates thyroid hormone secretion, and contributes to fol licular heterogeneity. (C) Societe francaise de biochimie et biologie molec ulaire / Elsevier, Paris.