Analysis of the molecular mechanisms of nuclear hormone receptors and corepressors

Nuclear hormone receptors (NHRs) function as ligand-regulated transcription factors that bind to specific DNA recognition sites denoted hormone response elements (HREs) and modulate the expression of adjacent target genes. Different receptors discriminate among different HREs by making sequence specific contacts with the DNA through a DNA binding domain (DBD) on the receptor polypeptide. I found out that N-terminal domains of NHRs can modify the ability of the receptor DBD to bind to HREs. For example, the N-termini of thyroid hormone receptors (T3Rs) help confer board DNA binding specificity to T3Rs; whereas the distinctive N-termini of retinoid X receptor isoforms help these receptors to recognize certain complex HREs. Therefore, the N-terminus of NHRs contribute to the distinct DNA binding specificities of these receptors and play important roles in differential target gene recognition.; Once NHRs bind the appropriate HREs, these receptors can either positively or negatively regulate the expression of target genes. Transcriptional repression by NHRs appears to require a physical interaction between receptors and a corepressor complex containing the N-CoR or SMRT polypeptides. I found out that different receptors interact with different domains in the N-CoR and SMRT corepressors, and that these divergent interactions may contribute to distinct repression phenotypes. I also reported that the SMRT corepressor can mediate transcriptional silencing through multiple mechanisms including: recruitment of histone deacetylases that are thought to modify the chromatin template, and interaction with general transcription factor TFIIB that may interfere with the function of preinitiation complex, resulting in transcriptional repression.; As key regulators of animal physiology, deregulation of NHR's functions have been linked to endocrine disease and cancer. Aberrant receptors, such as PLZF-RAR{dollar}alpha{dollar} oncoprotein is associated with human acute promyelocytic leukemia. The PLZF-RAR{dollar}alpha{dollar} receptor exhibits a novel pattern of association with corepressor SMRT. I found out that the PLZF moiety of the receptor can interact with the SMRT corepressor, correlating with the ability of normal PLZF protein to function as transcriptional repressor. Furthermore, BCL-6, another PLZF like transcriptional repressor also exhibits interactions with SMRT but in a distinctive manner, suggesting that transcriptional repression by BCL-6 and PLZF may differ in mechanism.