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Epigenomics and Epigenetics with Kristin and Mickey!
Transcript of Epigenomics and Epigenetics with Kristin and Mickey!
With Kristin and Mickey! Biochemical Background of Folates The homocysteine/methionine cycle THF Tetrahydrofolate (THF) is the biologically active form of folate. Folate is reduced to dihydrofolate, then again by dihydrofolate reductase to form tetrahydrofolate (THF). This process requires 2 NADPH .
Large amounts of THF are needed during periods of rapid cell growth
growth/expansion due to increased synthesis of DNA/RNA THF cont. Folate derivatives are involved in the methylation of DNA/RNA (protective) and the coversion of deoxyuridine to deoxythymidine, required for DNA/RNA synthesis.
Insufficient synthesis of THF reduces the rate of methionine re-synthesis, inducing homocysteine buildup. Folic Acid Function in various one-carbon transfer reactions, including purine and thymidlate biosynthesis, amino acid metabolism, and formate oxidation Folate: A Little History Folate is the form of folic acid (also known as vitamin B9, vitamin Bc or folacin) that is naturally occurring in the body
Foods high in folate include: Leafy vegetables, legumes, egg yolks, baker’s yeast, sunflower seeds, and liver and liver products
US Public Health Service recommends 0.4mg/day
In 1996, the FDA published regulations requiring the addition of folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products Folate: a clear factor in the incidence of NTDs Neural Tube Defects (NTDs)
Recurrent Early Pregnancy Loss
Fetal growth restriction/Low birth weight Homocysteine cycle S-adenosyl methionine (SAM) donates a methyl group to various biological substrates and is a key biochemical process. After methyl-donation, S-adenosyl homocysteine (SAH) is left. Homocysteine must be re-methylated to methionine (SAM) by methionine synthase, which requires methyl-cobalamin (methylated B12). N5-Methyl-THF donates the methyl group to cobalamin. This is a nucleus Random Spare Slide No real information here
You can take notes if you care to
But there's no point
Why did we make this slide again? See: shameless time-wasting. Also, see AEM curriculum for examples. DNA in the Nucleus DNA and Methylation Implications for public health Overall supplementation and effective dosage has yet to be clearly established, as it has the capacity to increase risk and progression
MTHFR C677T polymorphism high folate consumption may increase risk of colorectal cancer
Need to establish they are free of colorectal neoplasms prior to increasing folate dosage Kim YI. Role of folate in colon cancer development and progression. J Nutr. 2003;133(11 suppl 1):3731S–3739S. Folate Insuffiency leads to- Elevated homocysteine
Less DNA methylation
Altered gene expression
In vivo and in vitro-
Folate deficiency associated with DNA strand breaks, aberrant methylation, increased mutations
May be corrected through supplementation Kim YI. Role of folate in colon cancer development and progression. J Nutr. 2003;133(11 suppl 1):3731S–3739S. Epigenetics and Cancer MTHFR C677T polymorphism reduces overall DNA methylation, as there are higher levels of 5, 10-methyltetrahydrofolate and lower levels of 5-methyltetrahydrofolate Kim YI. Role of folate in colon cancer development and progression. J Nutr. 2003;133(11 suppl 1):3731S–3739S. After cancer development.. Folate supplementation was found to increase progression of established neoplasms
Therefore, timing of folate intervention dictates how cancer may begin and how it may progress Kim YI. Role of folate in colon cancer development and progression. J Nutr. 2003;133(11 suppl 1):3731S–3739S. Nutrition and Implications Epigenetic mechanisms for nutrition determinants of later health outcomes Background information
We will discuss both salient nutrition and implications in terms of the paper
For your understanding Epigenetic mechanisms for nutrition determinants of later health outcomes Quiz!
Win a prize for a correct answer
Lose your dignity for every wrong answer (candy thrown toward and/or around your face with intent to maim). Epigenetic mechanisms for nutrition determinants of later health outcomes
QUIZ 7. What are the roles of folate, choline? How does this compare with the role of methionine in DNA methylation? 9. What would you recommend for a pregnant woman with a G195A SNP in MTHFD1? 1. How many SNP’s are found in each individual genome? 2. What is responsible for differential gene expression in tissues? 3. In what state are histones accessible to transcription factors? 4. What is the role of methyltransferases in DNA and what are the possible consequences of improper activity? 8. What is the link between estrogen and choline biosynthesis? 5. Will hypermethylation of a DNA always silence a gene? 6. What DNA base is methylated by methyltransferase? 1. 50,000
2. DNA methylation of CpG islands
3. Methylated/acetylated to promote transcription
4. Donate methyl groups to new strand during replication
5. No, it must occur in specific regulatory regions (CpG Islands)
7. Methionine is a methyl accepter and donator, and receives methyl from the metabolism and processing of folate and choline.
8. Estrogen upregulates PEMT
9. Choline supplementation Neural Tube Defects and Folate High maternal choline diet has been associated with a reduction in neural tube defects
For more than 10 years, all flour and cereal products in the US have been fortified with Folic Acid
MTHFD1 G1958A SNP reduces the amount of 5-methyl tetrahydrofolate for homocysteine remethylation
Diet demands for higher levels of choline The homocysteine/methionine cycle Epigenetics and Cancer
Therefore, 677TT genotype demands higher levels of folate
Decrease in the conversion from 5,10 to 5 leads to increase in homocysteine levels and DNA hypomethylation
Polymorphism has been associated with increase in colorectal cancer risk Kim YI. Role of folate in colon cancer development and progression. J Nutr. 2003;133(11 suppl 1):3731S–3739S. Answers Nutritional Implications Methylation and Transcription DNA Methyltransfase 'Dat Paper Studies in the 1950s and 1960s first led to recognition of prenatal folic acid supplementation as a means to prevent pregnancy induced megaloblastic anemia and NTDsIn the 1990s, more conclusive evidence led to the widespread enforcement of folic acid fortificationThe complete etiology of folate in relationship to reproductive effects is still yet to be determined Folate: A Little History Hcy Buildup Dangers Folate deficiency induces neurotoxicity by extracellular Hcy buildup, which induces cellular oxidative stress, cytosolic calcium increases, and mitochondrial and DNA damage. Will be discussed later Dna is bound in the nucleus as chromatin, wrapped about proteins called histones, which may be methylated or acetylated to allow access to DNA by transcription factors. This structure (DNA+protein) is called a nucleosome. DNA itself can be methylated by special proteins called DNA methyltransferases. They act by donating the methyl groups gained in the homocysteine/methionine cycle to a cytosine on DNA.
Methylating DNA has several uses, including protective and functional purposes. Substrates DNA Methyltransferase Cytosine Methylation occurs on most cytosines throughout the genome.
If methylation occurs at regulatory 5' -ends of genes which are normally unmethylated, called CpG islands, then the gene is silenced. CpG Islands Despite methylation status on exonic, intergenic, or transposon regions, methylation of CpG will indicate transcription or suppression of a gene.
Likely explains how some genes are expressed in some tissues but not in others. E.g. Additional X chromosome in women: DNA hypermethylated at CpG Islands but hypomethylated throughout the rest of the chromosome. In Vivo? Indeed-o