Project description:Sex differences in liver gene expression are dictated by sex-differences in circulating growth hormone (GH) profiles. Presently, the pituitary hormone dependence of mouse liver gene expression was investigated on a global scale to discover sex-specific early GH response genes that might contribute to sex-specific regulation of downstream GH targets and to ascertain whether intrinsic sex-differences characterize hepatic responses to plasma GH stimulation. RNA expression analysis using 41,000-feature microarrays revealed two distinct classes of sex-specific mouse liver genes: genes subject to positive regulation (class-I) and genes subject to negative regulation by pituitary hormones (class-II). Genes activated or repressed in hypophysectomized (Hypox) mouse liver within 30-90min of GH pulse treatment at a physiological dose were identified as direct targets of GH action (early response genes). Intrinsic sex-differences in the GH responsiveness of a subset of these early response genes were observed. Notably, 45 male-specific genes, including five encoding transcriptional regulators that may mediate downstream sex-specific transcriptional responses, were rapidly induced by GH (within 30min) in Hypox male but not Hypox female mouse liver. The early GH response genes were enriched in 29 male-specific targets of the transcription factor Mef2, whose activation in hepatic stellate cells is associated with liver fibrosis leading to hepatocellular carcinoma, a male-predominant disease. Thus, the rapid activation by GH pulses of certain sex-specific genes is modulated by intrinsic sex-specific factors, which may be associated with prior hormone exposure (epigenetic mechanisms) or genetic factors that are pituitary-independent, and could contribute to sex-differences in predisposition to liver cancer or other hepatic pathophysiologies.
Project description:Thyroid hormone (TH) serves as a master regulator in our body, governing body metabolism and growth. Circulating TH level has been demonstrated to correlate with cardiac regenerative potential by modulating cell-cycle arrest and polyploidization in cardiomyocytes (CMs), while the molecular mechanism is still unknown. Here, we investigated the molecular mechanisms of TH signalling on heart regeneration through a time-course sequencing experiment. We disrupted the TH signalling in a zebrafish model by thyroid hormone receptor alpha a (thraa) knockout (KO). The thraa-KO zebrafish demonstrated an accelerated heart regenerative process, indicating that TH through thyroid hormone receptors (TRs) impaired heart regeneration. Our study discovered that diminished TH signalling in thraa-KO zebrafish alters the pro-inflammatory response and the regenerative process of cardiac tissue through myocardial metabolic switch. Moreover, TH signalling was shown to modulate the restoration of hypoxic response via hif3a. Altogether, our study highlighted that the role of TH signalling in modulating the progress of heart regeneration in zebrafish.
