Liganded Thyroid Hormone Receptor Induces Nucleosome Removal and Histone Modifications to Activate Transcription during Larval Intestinal Cell Death and Adult Stem Cell Development

Abstract

Thyroid hormone (T₃) plays an important role in regulating multiple cellular and metabolic processes, including cell proliferation, cell death, and energy metabolism, in vertebrates. Dysregulation of T₃ signaling results in developmental abnormalities, metabolic defects, and even cancer. We used T₃-dependent Xenopus metamorphosis as a model to study how T₃ regulates transcription during vertebrate development. T₃ exerts its metamorphic effects through T₃ receptors (TR). TR recruits, in a T₃-dependent manner, cofactor complexes that can carry out chromatin remodeling/histone modifications. Whether and how histone modifications change upon gene regulation by TR during vertebrate development is largely unknown. Here we analyzed histone modifications at T₃ target genes during intestinal metamorphosis, a process that involves essentially total apoptotic degeneration of the simple larval epithelium and de novo development of the adult epithelial stem cells, followed by their proliferation and differentiation into the complex adult epithelium. We demonstrated for the first time in vivo during vertebrate development that TR induces the removal of core histones at the promoter region and the recruitment of RNA polymerase. Furthermore, a number of histone activation and repression marks have been defined based on correlations with mRNA levels in cell cultures. Most but not all correlate with gene expression induced by liganded TR during development, suggesting that tissue and developmental context influences the roles of histone modifications in gene regulation. Our findings provide important mechanistic insights on how chromatin remodeling affects developmental gene regulation in vivo.