AUTOREGULATION OF THYROID-SPECIFIC GENE-TRANSCRIPTION BY THYROGLOBULIN

Thyroglobulin (TG), the primary synthetic product of the thyroid, is t he macromolecular precursor of thyroid hormones. TG synthesis, iodinat ion, storage in follicles, and degradation control thyroid hormone for mation and secretion into the circulation. Thyrotropin (TSH), via its receptor (TSHR), increases thyroid hormone levels by upregulating expr ession of the sodium iodide symporter (NIS), thyroid peroxidase (TPO), and TG genes. TSH does this by modulating the expression and activity of several thyroid-specific transcription factors, thyroid transcript ion factor (TTF)-1, TTF-2, and Pax-8, which coordinately regulate NIS, TPO, TG, and the TSHR. Major histocompatibility complex class I gene expression, which also is regulated by TTF-1 and Pax-8 in the thyroid, is decreased simultaneously. This helps maintain self-tolerance in th e face of TSH-increased gene products necessary for thyroid hormone fo rmation. In this report we show that follicular TG counter-regulates T SH-increased, thyroid-specific gene transcription by suppressing expre ssion of the TTF-1, TTF-2, and Pax-8 genes. This decreases expression of the TG, TPO, NIS, and TSHR genes, but increases class I expression. TG acts transcriptionally, targeting, for example, a sequence within 1.15 kb of the 5' flanking region of TTF-1. TG does not affect ubiquit ous transcription factors regulating TG, TPO, NIS, and/or TSHR gene ex pression. The inhibitory effect of TG on gene expression is not duplic ated by thyroid hormones or iodide and may be mediated by a TG-binding protein on the apical membrane. We hypothesize that TG-initiated, tra nscriptional regulation of thyroid-restricted genes is a normal, feedb ack, compensatory mechanism that limits follicular function and contri butes to follicular heterogeneity.