METHYL METABOLISM 2002

METHYL METABOLISM 2002: EPIGENETICS, GENOMICS, PROTEOMICS; SILENCING ìBADî AND ACTIVATING ìGOODî DNA, mRNA TRANSCRIPTS, AND THEIR PROTEINS, BY SELECTIVE TARGETED CHROMATIN METHYLATION AND DEMETHYLATION. Victor Herbert, MD. Mt. Sinai-NYU Health System & Bronx V.A. Med Ctr, Bronx, NY, 10468.

Bacteria auxotrophic for methionine, deprived of it, make less methylated RNA, which is synthesized more rapidly (Borek,1954). In ìThe Inhibition of Some Cancers and the Promotion of Others by Folic Acid, Vitamin B₁₂, and Their Antagonistsî (Herbert V. In: Nutritional Factors in the Induction and Maintenance of Malignancy [Butterworth CE, Hutchinson ML, Eds.]. NY Acad Press, 1983:273-287), we reviewed that this also occurs in humans, treating sickle cell disease by producing folate deficiency, activating a sharp rise in fetal, and fall in sickle, hemoglobin. We concluded: ìI should like to suggest the hypothesis that deficiency of folate or vitamin B₁₂, or any other cause of failure to methylate DNA and/or RNA, can activate malignancy by hypomethylation of oncogenes, and that methylating oncogenes can inhibit malignancy by making them dormant.î The NIH August 6-8, 2001, Trans HHS Workshop, ìDiet, DNA Methylation Processes, and Healthî confirmed that any DNA, RNA, or proteome allele, normal or variant, can be activated by demethylation (by methyl deficiency, 5-azacytidine, etc) or silenced by methylation, through transcriptional repressive protein complexes (and their inactivating antibodies) such as Dnmts (DNA methyltransferases) and HDACs (histone deacetylases). Non-targeted methylation suppresses cancer by suppressing oncogenes and/or their product RNAs and/or proteins, and promotes cancer by suppressing tumor suppressor genes, RNAs, and proteins which suppress angiogenesis, metastasis, and cancer cell DNA repair genes. Targeted methylation (A Wolffe, F Urnov, [Trans HHS Workshop, supra]can selectively epigenetically silence, with tailored zinc finger ìbullets,î solely the disease-promoting regions in cells, i.e. the unique gene variant chromatin nucleotide sequences (single nucleotide polymorphisms) (SNPs, travelling in groups [haplotypes]). Using high-throughput instrumentation (C M Henry. Pharmacogenomics. Chem & Eng News, 2001; 79 (33): 37-42), one can detect these diagnostic sequences from a small sample before clinical stigmata appear, and, by targeted methylation, silence the detected gene variant chromatin.

Presented at both 2002 FASEB Summer Research Conference on "Folic Acid, Vitamin B12 and One Carbon Metabolism", Snowmass Village, Colorado, Aug 3-8, 2002, and 29^th World Congress, International Soc Hematology, Aug 24-28, 2002, Seoul, South Korea.