Nuclear Receptor Genes - Regulation and Evolution

Abstract

Nuclear receptors are transcription factors that typically bind ligands in order to regulate the expression level of their target genes. Members of this family work with their co-regulators and repressors to maintain a variety of biological and physiological processes such as metabolism, development and reproduction. Nuclear receptors are promising drug targets and have therefore attracted immense attention in recent decades in the field of pharmacology. Irregular expression of nuclear receptor genes is linked to various metabolic and proliferative diseases such as cancer, diabetes and obesity. Despite extensive study in this area, how nuclear receptor genes are regulated is still poorly understood. As regulators of other genes, nuclear receptors and their activites are tightly regulated themselves. We propose that diversity of their biological and biochemical roles will be reflected in fundamental differences of their transcription regulation mechanism. We aimed to study the impact of regulatory content and evolutionary history of nuclear receptors genes on their expression and current function. To facilitate this work we used the Genomic Regulatory Block (GRB) for studying regulation of nuclear receptor genes in connection with their known function. In this thesis, I present a new classification of nuclear receptor genes on the basis of their cis-regulatory environment. We identified the nuclear receptor genes that are putative targets of long-range gene regulation. These genes are involved with developmental related functions and are characterized by the presence of highly conserved non-coding elements, CpG islands, bivalent promoter marks and specific combinatorial patterns of histone modifications. We also explored the evolutionary history of nculear receptor genes in context to our proposed classificiation. We found that nuclear receptors genes that are under long-range gene regulation exhibit negative selection pressure in comparison to GRB non-target genes. This is suggestive of an evolutionary constraint and shows that the functions of nuclear receptors have been recruited since the ancestral time.