ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: PLoS Genet. 2020;16:e1008770.

Præstholm et al. quantified by a genomics approach histone H3 acetylation – an epigenetic mark for DNase accessible chromatin – at thyroid hormone target gene enhancers to challenge the current model of genome binding action of T3 (type 1 action of thyroid hormone receptors (TR)) [1]. For this, they investigated genome-wide the liver of WT mice at hypothyroid and hyperthyroid state. First, they observed that less than 40% of genomic regions that became hyperacetylated in response to T3 contained T3 response elements (TRE). Second, comparing WT vs. TR inactive tissues, hyperacetylation in response to T3 only occurred in TRE negative regions in the presence of functional TR. Finally, they revealed that T3 hyperacetylated enhancers without TRs and TREs were activated indirectly by co-association with TR bound enhancers in a higher order organization of hyperacetylated enhancers either at short distance to super-enhancers, or at large distance to topological associated domains.

Until now, a bimodal switch model was generally accepted to describe TR activation of enhancers of thyroid hormone target genes by direct binding to the genome at TREs (type 1 action of TR) [1]. Based on the current results, the authors propose a new and more differentiated concept than the bimodal switch, describing T3 dependent enhancer activation mediated by H3 hyperacetylation. The concept integrates 3 mechanisms: A) poised enhancers hyperacetylated upon dissociation of co-repressors and recruitment of co-activators, B) dormant enhancers hyperacetylated upon T3 dependent TR and co-activator recruitment to chromatin, and C) Non TR containing enhancers hyperacetylated by T3 activation of TR occupied enhancers at distance in the context of higher order chromatin structure.

These important data add to current knowledge a more differentiated mechanistic concept of type 1 T3 induced target gene transcription. They show in detail how epigenetic mechanisms, such as acetylation, are involved in thyroid hormone action. Beyond thyroid hormones, these data highlight the complexity of hormone dependent gene regulation possibly also functional for estrogen or vitamin D.

Reference:

1. Flamant F, Cheng S-Y, Hollenberg AN, Moeller LC, Samarut J, Wondisford FE, Yen PM, Refetoff S. Thyroid hormone signaling pathways: time for a more precise nomenclature. Endocrinology. 2017;158:2052–57.