Monoamine oxidases (MAO) A and B (EC 1.4.3.4) oxidize catecholamine and indoleamine neurotransmitters and may play roles in neurologic and psychosocial disorders, including Parkinson's Disease, schizophrenia, depression and alcoholism, and in the neurotoxicity of MPTP. Therefore, the reported 10- to 100-fold variability reported in MAO A and B activities between individuals could be a factor in human health. Inter-individual variability could arise from differences in the cis regulatory elements of the MAO genes or to differences in the action of other genes which act upon these elements. In order to investigate the possible involvement of transcriptional mechanisms in inter-individual variability of MAO A and B, we must know more about the basic molecular mechanisms which regulate the MAO A and B genes. MAO A and B exhibit complex , overlapping patterns of cell type-specificity and are regulated differently by steroid hormones. Our recent sequencing of the MAO A and B promoter regions provides the first opportunity to investigate the mechanisms of MAO A and B gene regulation. To understand how sequence differences in the MAO A and B promoters and associated DNA regions contribute to cell type-specificity, hormone responsiveness, and inter-individual variability, we propose to (1) further characterize expression of the MAO A and B genes in selected cell lines, (2) extend the known sequence of the cloned MAO A and B promoter regions and establish the transcription start sites;, (3) localize and test the role of DNA sequence elements in and around the promoter in the activity of the MAO A and B promoters in cells which express the corresponding, endogenous MAO genes; (4) evaluate the cell type-specificity of the promoter and enhancer elements identified in aim 3, (5) map DNase I hypersensitive sites in the MAO A and B promoter and surrounding regions in chromatin, and (6) determine whether the MAO A gene subject to X chromosome inactivation, and whether differences in X-linked sequence elements contribute to inter-individual variability in MAO A activities. Accomplishment of these aims will clarify how two, closely linked genes which have diverged from a common ancestral gene have evolved the independent and complex cell type-specificity and hormonal responsiveness characteristic of MAO A and B, and test the role of primary transcriptional mechanisms in the potentially important variation of MAO A and B in the human population.
Showing the most recent 10 out of 13 publications
