ESPE Yearbook of Paediatric Endocrinology

Nat Commun. 2021 Jul 21;12(1):4446. doi: 10.1038/s41467-021-24748-8. PMID: 34290257

Brief Summary: Jaundice is a major clinical sign of congenital hypothyroidism. LT4 treatment in hypothyroid neonates normalizes jaundice rapidly by inducing hepatocyte maturation. This mouse model study investigated the molecular mechanisms of thyroid hormone induced hepatocyte differentiation. A postnatal activation of type 2 deiodinase (Dio2) resulted in a T3 surge between postnatal day 1 and 10, inducing permanent hepatocyte specific gene expression mediated by DNA demethylation.

In many developing organs, the local T3 concentration is kept low during fetal development. Differentiation in several organs has been linked to upregulation of tissue specific DIO2 expression and increase in tissue T3 concentration (e.g. retina) [1]. Liver specific Dio2 inactivation (Alb-D2KO) resulted in low T3 signaling during postnatal day 1 and 5, and led to de novo DNA hypermethylation. Consequently, the Alb-D2KO liver showed permanently reduced chromatin accessibility in 1551 promoters, and 2426 intragenic regions, and 1363 downregulated genes compared to control liver tissues. Besides reduced chromatin accessibility at promotors, the authors also found evidence for disturbed long-distance chromatin interactions being involved in such fundamental changes of gene expression in Alb-D2KO livers.

In summary, these data provide important insights into the Dio2 mediated postnatal T3 surge, which was found to induce epigenetic regulation and hepatocyte differentiation. They extend current knowledge on the role of DNA demethylation for liver specific gene expression [2].

References: 1. Thyroid hormone signaling specifies cone subtypes in human retinal organoids. Eldred KC, Hadyniak SE, Hussey KA, Brenerman B, Zhang PW, Chamling X, Sluch VM, Welsbie DS, Hattar S, Taylor J, Wahlin K, Zack DJ, Johnston RJ Jr. Science. 2018 Oct 12;362(6411):eaau6348. doi: 10.1126/science.aau6348. PMID: 30309916. 2. Postnatal DNA demethylation and its role in tissue maturation. Reizel Y, Sabag O, Skversky Y, Spiro A, Steinberg B, Bernstein D, Wang A, Kieckhaefer J, Li C, Pikarsky E, Levin-Klein R, Goren A, Rajewsky K, Kaestner KH, Cedar H. Nat Commun. 2018 May 23;9(1):2040. doi: 10.1038/s41467-018-04456-6. PMID: 29795194.