Biochemistry and Cell Biology = Biochimie Et Biologie Cellulaire
My desire as a young endocrinologist to improve my clinical skills through a better knowledge of hormone chemistry led me to serendipitous discoveries and unexpected horizons. The first discovery, published in 1967, revealed that peptide hormones are derived from endoproteolytic cleavages of larger precursor polypeptides. It was the foundation of the prohormone theory.
Many hormonal signals from peripheral tissues contribute to the regulation of energy homeostasis and food intake. These regulators including leptin, insulin, and ghrelin, modulate the orexigenic and anorexigenic neuropeptide expression in hypothalamic nuclei. The anti-aging effects of caloric restriction have been explained from an evolutional viewpoint of the adaptive response of the neuroendocrine and metabolic response systems to maximize survival during periods of food shortage.
Elevated LDL-cholesterol is a risk factor for the development of cardiovascular disease. Thus, proper control of LDL-cholesterol homeostasis is critical for organismal health. Genetic analysis has identified PCSK9 (proprotein convertase subtilisin/kexin type 9) as a crucial gene in the regulation of LDL-cholesterol via control of LDL receptor degradation. Although biochemical characteristics and clinical implications of PCSK9 have been extensively investigated, epigenetic regulation of this gene is largely unknown.
Reln mRNA and protein levels are reduced by approximately 50% in various cortical structures of post-mortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. To study mechanisms responsible for this down-regulation, we have analyzed the promoter of the human reelin gene. We show that the reelin promoter directs expression of a reporter construct in multiple human cell types: neuroblastoma cells (SHSY5Y), neuronal precursor cells (NT2), differentiated neurons (hNT) and hepatoma cells (HepG2).
Covalent modifications of DNA and its surrounding chromatin constitute an essential and powerful regulatory mechanism for gene transcription. Epigenetics is the study of this regulatory system. There is now strong albeit indirect evidence that epigenetic mechanisms contribute to the pathophysiology of schizophrenia. Furthermore, the discovery that valproic acid, a widely used psychotropic, has powerful epigenetic effects in clinically relevant concentrations suggests new therapeutic possibilities, i.e., drugs that act on chromatin structure.
Proceedings of the National Academy of Sciences of the United States of America
The polygenic nature of complex psychiatric disorders suggests a common pathway that may be involved in the down-regulation of multiple genes through an epigenetic mechanism. To investigate the role of methylation in down-regulating the expression of mRNAs that may be associated with the schizophrenia phenotype, we have adopted a cell-culture model amenable to this line of investigation.
American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics
DNA methylation changes could provide a mechanism for DNA plasticity and dynamism for short-term adaptation, enabling a type of cell memory to register cellular history under different environmental conditions. Some environmental insults may also result in pathological methylation with corresponding alteration of gene expression patterns.
American Journal of Pharmacogenomics: Genomics-Related Research in Drug Development and Clinical Practice
No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms.
A recent report suggests that the down-regulation of reelin and glutamic acid decarboxylase (GAD(67)) mRNAs represents 2 of the more consistent findings thus far described in post-mortem material from schizophrenia (SZ) patients [reviewed in. Neurochemical markers for schizophrenia, bipolar disorder amd major depression in postmortem brains. Biol Psychiatry 57, 252-260]. To study mechanisms responsible for this down-regulation, we have analyzed the promoter of the human reelin gene.
Reelin and glutamic acid decarboxylase 67 (GAD67) mRNAs and protein levels are substantially reduced in postmortem brains of patients with schizophrenia. Increasing evidence suggests that the observed down-regulation of reelin and GAD67 gene expression may be caused by dysfunction of the epigenetic regulatory mechanisms operative in cortical GABAergic interneurons.