Thyroid hormone action during development

Abstract

NaTure reviews | Endocrinology In this study, TH signalling permanently affects intergenic enhancers Developmental DIO2-generated T3 signalling permanently affects remote enhancers and gene expression. R, receptor. Rachael Tremlett/Springer Nature Limited The mechanisms by which thyroid hormone (TH) signalling affects development are unclear. Now, a study published in Nature Communications shows how systemic T3 acts locally in the liver during development to permanently modify hepatic gene expression. During development, TH signalling can be regulated in different tissues by coordinated deiodinase expression. “Deiodinases can activate and inactivate TH, thus they can amplify TH signalling (via DiO2) or terminate TH action (via DiO3),” explains corresponding author antonio Bianco. “we hypothesized that perinatal DiO2 inactivation leads to DNa methylation by accelerating triple methylation of the histone H3K9; increased DNa methylation leads to the formation of heterochromatin, reducing DNa accessibility, which in turn leads to reduced gene expression.” The researchers studied development in wild-type and liver-specific Dio2-deficient mice, using chromatin immunoprecipitation sequencing to study histone methylation, aTaC-seq to study chromatin accessibility and rNa-seq to study gene expression. in wild-type mice, a neonatal peak of DiO2 activity occurs in hepatoblasts, which increases TH signalling and prevents the triple methylation of H3K9. However, in liver-specific Dio2-deficient mice, H3K9 becomes transiently triple-methylated during development, resulting in methylation of 1,508 DNa sites in adult mouse liver. These sites were associated with reduced chromatin accessibility in many promoters and intergenic regions, and reduced expression of 1,363 genes. “when thinking of TH signalling, we have always considered nearby enhancers, such as those located within 5 kbp of the promoter region, and reversible regulation,” explains Bianco. “in this study, TH signalling permanently affects intergenic enhancers, which are T H Y R O I D F U N C T I O N