Genome-wide analysis of DNA methylation and its regulation by hormones during post-embryonic brain development

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

The goal of this project is to advance understanding of brain development by studying a novel role of thyroid hormone (TH) in the regulation of gene expression in early development. It is known that the expression of genes is controlled in part by chemical modifications to deoxyribonucleic acid (DNA) and the proteins that surround the DNA. These so-called 'epigenetic modifications' result in heritable changes in gene function that do not involve changes to the DNA sequence itself. Recent findings show that epigenetic modifications play pivotal roles in organismal development, physiology, and behavior, and are implicated in human diseases from cancer to complex behavioral disorders, such as autism and schizophrenia. One such epigenetic modification is the addition of methyl groups to cytosine residues in DNA (DNA methylation). Variable DNA methylation at gene regulatory regions can influence gene expression. DNA methylation typically promotes gene repression, whereas DNA demethylation promotes gene activation. However, the patterns and functions of DNA methylation in the brain during development, and the factors that control DNA methylation are poorly understood. The Principal Investigator (PI) recently discovered that TH, which is known to be critical for normal development of the central nervous system, controls DNA methylation in the developing brain. Here, he will examine the mechanism of DNA methylation by TH and its consequences for neurological development using the frog as model system. The project also will involve training of a diverse scientific workforce, establishment of an undergraduate course in experimental design for life scientists, and science outreach activities with middle school students and with adults at retirement communities. The specific aims of this project are to: 1) map DNA methylation patterns in the developing brain using genome-wide analyses including RNA sequencing, chromatin immunoprecipitation sequencing, and methyl capture sequencing, 2) determine the mechanisms by which TH regulates DNA methylation using targeted analysis of TH-dependent recruitment of enzymes to chromatin, and 3) understand the consequences of TH regulation of DNA methylation for neurological development through analysis of cell cycle control. The PI will focus on metamorphosis of the frog Xenopus (Silurana) tropicalis, a well studied TH-dependent process. They will conduct genome-wide methylation and transcription factor association analyses to investigate the patterns and roles of DNA methylation during postembryonic brain development. The results of the proposed research will provide a deeper understanding of factors that modulate the epigenetic landscape in neural cells, and will open new avenues for research on the regulation and roles of DNA methylation in neurological development and function.