Are you the way you are because of the

Transcription

1 EPIGENETICS

2 Are you the way you are because of the It s my fault!! Nurture Genes you inherited from your parents? Nature Experiences during your life?

3 Similar DNA Asthma, Autism, TWINS Bipolar Disorders Healthy Same Environment

4 Nurture DNA IS NOT OUR DESTINY! Not my fault Nature Epigenetics Heritable changes in gene expression without involving changes to the underlying DNA sequence: a change in phenotype without a change in genotype

5 Genetic Information provides the building block (gene-segment of DNA) for the manufacture of all Proteins needed for cell function activity Epigenetic Information provides instructions on how, where and when the genetic information should be used

6 Human Genome 3 billion base pairs of DNA packed in 23 chromosomes Cells in the body are diploid (except for female ova and male sperm): 23 pairs of chromosome. 6 billion base pairs of DNA (or 2 meters) per cell Human body contains 50 trillion cells 100 trillion meters of DNA per human Pierce B et al Genetics: A Conceptual Approach, 2 nd ed.

7 Nucleosome 146 base pairs of DNA wrapped around the core (contains 8 histone molecules, two each from four of the histone classes) H1 10 nm chromatin fiber Prokaryotic &eukaryotic chromosome structure in Instant Notes in Molecular Biology(3rd Edition) Histone H1 Clamps the DNA to the core and compact the nucleosome into the 30nm fiber

8 DNA Methylation Addition of a methyl (CH3) group to the cytosine ring, resulting in 5-methylcytosine (5- mc). 5-mc occurs in a CpG site, in which cytosine nucleotide is located next to guanidine nucleotide DNMT: DNA methyltransferase; SAM: S-adenosylmethionine

9 Histone Modifications Histone proteins have N-terminal tails that project into the liner DNA. Histone tails are subject to a variety of covalent modifications which can yields different chromatin structure, and therefore will affect gene expression. Perla Cota, Stem Cells and Epigenetic Reprogramming

10 Perla Cota, Stem Cells and Epigenetic Reprogramming

11 Histone acetylation the addition of acetyl moieties onto each of the histones of the nucleosome and is regulated by the activity of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Active HDACs serve to remove the acetyl moiety from the histone tail through a chargerelay system of residues found within the active site. Once removed, the histones bind tighter to the DNA as well as enabling tighter packing of adjacent histones leading to more transcriptional repression Perla Cota, Stem Cells and Epigenetic Reprogramming

12 Decreased oncogene methylation immune evasion Increased tumor suppressor methylation cancer cell proliferation normal cell Reactive O 2 + N 2 Cells blood vessel Cytokines chemokines Cancer cell migration, invasion and metastasis

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14 The mammalian epigenome undergoes global remodeling during early stem cell development that requires commitment of cells to be restricted to the desired lineage. No many epigenetic marks The maintenance of the lineage commitment of stem cells are controlled by epigenetic mechanisms: e.g., distinct covalent histone modifications can lead to functionally distinct chromatin structures that influence the fate of the cell.

15 Epigenetic marks can be influenced by the environment

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17 Some studies show that supplementation with methyl donors such as folate, choline and vitamin B12 may influence DNA methylation and may have beneficial effect on CVD risk, but results are still inconsistent

18 Epigenetic marks can be transmitted to multiple generations Magnitude of change in food availability If the paternal grandmother up to puberty lived through a sharp change in food supply from one year to next, her sons daughters had an excess risk for cardiovascular mortality (HR 2.69, 95% confidence interval ) Bygren LO et al. 2014, BMC genetics

19 Epigenetic marks can accumulate after birth Weaver ICG et al. 2004, Nature Neuroscience

20 HDACs Inactive ACTIVATION

21 Activate HDACs REPRESSION

22 EPIGENETICS Brain Inflammato ry disease Cancer Cardiovas ular disease

23 Targets for Clinical Markers and Therapeutic intervention SNPs/CNVS DNA methylation DNA Genetic effect RNA interference RNA Histone mdofication Protein Epigenetic effect Change in cell/organ function => Disease

24 Genetic, Epigenetic and Transcriptional Variants SNP is more likely to: (1) affect a methyl site that, in turn, affects gene expression levels (2) affect gene expression levels that, in turn, affects DNA methylation (3) affect both gene expression and methylation independently of one another Gutierrez-Arcelus M et al In all three tissues tested, it is more likely that a SNP affects methylation and expression independently, with SNP to expression to methylation being the least likely in all cases. SNP interferes with or alters a TF binding site, and could potentially affect both DNA methylation and gene expression independently

25 Global DNA-methylation Global methylation refers to the overall level of methylcytosine in the genome, expressed as percentage of total cytosine. A large portion of methylation sites within the genome are found in repeat sequences and transposable elements, such as Alu and longinterspersed nuclear element (LINE-1) and correlate with total genomic methylation content

26 Global DNA-methylation: as a biomarkers?!

27 Global DNA-methylation: how functionally such a measure could be useful?! LINE-1 and Alu repeats represent distinct measures of dispersed DNA methylation, and might have different functions. The quantitative assessment of DNA methylation at ALU is about one-third to one-fourth of methylation at LINE-1, which may suggest that epigenetic changes at LINE-1 and ALU might measure different traits Methylation has a different effect depending on its position towards coding genes

28 Gene expression: depends on where within the gene sequence the methylation occurs DNA methylation in the promoter region of the gene downregulates its expression whereas higher methylation in the genebody promotes the expression of the gene Ndlovu MN et al. 2011, Trends in Biochemical Sciences

29 DNA methylation in several genomic contexts varies substantially among human tissues Shultz MD et al. 2013, Nature

30 Tissue-Specific variation No difference in global DNA methylation in PBMCs(comprising both lymphocytes and monocytes), or in the lymphocyte or monocyte populations assessed separately was found between T2D cases and non-t2d controls. In T2D patients, compared to controls, there was an increased methylation levels in B (p=0.022) and natural killer cells (p=0.004) but not in T helper (p>0.05) and T cytotoxic cells (p>0.05).

31 Gene-specific methylation

32 Gene-specific methylation

33 Gene-specific methylation The strong association of smoking with CVD-outcomes was markedly attenuated when the analysis were corrected for F2RL3 methylation intensity

34 Gene-specific methylation ABCA1 gene methylation is associated with plasma glucose, HDL levels and the presence of cardiovascular disease.

35 Gene-specific methylation F7 and tumor necrosis alpha gene methylation is associated with plasma FACTOR VII concentrations and body weight respectively and the presence of cardiovascular disease.

36 Gene-specific methylation Several studies have revealed methylation of specific genes to be associated with type 2 diabetes.

37 GLP1R Gene in pancreatic β cell Increased expression of GLP1R Decreased DNA methylation Increased insulin secretion and decreases glucose levels Management of hyperglicemia in T2D?!

38 » The study of epigenetic markers is emerging as one of the most promising molecular strategies for risk stratification for complex disease, and when implemented will have a sizable public health impact.» As epigenetic DNA modifications are potentially reversible and may be influenced by nutritional-environmental factors and through gene environment interactions, future therapies targeting epigenome can be a novel preventive strategy and treatment for chronic disease.