Epigenomics Epi Geromics Jong Bhak Epigenetic Chromatin Structure

Epigenomics Epi. Geromics Jong Bhak

Epigenetic Chromatin Structure • Most epigenetic research has converged on the study of covalent and noncovalent modifications of DNA and histone proteins as the mechanisms that directly influence chromatin structure. • https: //www. youtube. com/watch? v=M 4 bo. Kud 1 MRk

Chromatin structure Gene Expression • This is because the local chromatin environment of a given gene strongly influences its expression.

Definition: Epigenomics • is the study of the complete set of epigenetic modifications on the genetic material of a cell, known as the epigenome.

Reversible • Epigenetic modifications are reversible modifications on a cell’s DNA or histones that affect gene expression without altering the DNA sequence. • Modificaion affects Next generation • Cloning

Differentiation and Development & Tumorigenesis. • Epigenetic modifications play an important role in gene expression and regulation, and are involved in numerous cellular processes such as in differentiation and development and tumorigenesis.

Epi. Geromics. • Epigenetic modifications play an important role in gene expression and regulation, and are involved in numerous cellular processes such as in differentiation and development and senescence.

Epigenomics Mechanisms RNA Interference Gene Expression Histone Modifications DNA Methylation DNA methylation, histone modifications, chromatin accessibility & small RNA transcripts

DNA Methylation Hypomethylation Hypermethylation http: //www. cellscience. com/reviews 7/Taylor 1. jpg

DNA methyltransferase The DNA methyltransferase (DNA MTase) family of enzymes catalyze the transfer of a methyl group to DNA methylation serves a wide variety of biological functions. All the known DNA methyltransferases use S-adenosyl methionine (SAM) as the methyl donor.

DNA (cytosine-5)methyltransferase 1 is an enzyme that in humans is encoded by the DNMT 1 gene. Function DNA (cytosine-5 -)-methyltransferase 1 has a role in the establishment and regulation of tissue-specific patterns of methylated cytosine residues. Aberrant methylation patterns are associated with certain human tumors and developmental abnormalities.

crystal structure of type i restriction enzyme ecoki m protein (ec 2. 1. 1. 72) (m. ecoki)

S-Adenosyl methionine (SAM-e, SAM, SAdenosyl-L-methionine, Ado. Met, ademetionine) is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952

Natural Roles of DNA Methylation in Mammalian System Ø Imprinting Ø X chromosome inactivation Ø Heterochromatin maintenance Ø Developmental controls Ø Tissue specific expression controls

Heterochromatin

DNA Methylation and Cancer Robertson, Nature Reviews Genetics, Vol 6, 597

DNA Methylation and Aging -- Imprinting Disorder: • Beckwith-Wiedemann syndrom (BWS) • Prader-Willi syndrome (PWS) • Transient neonatal diabetes mellitus (TNDM) -- Repeat-instability diseases • Fragile X syndrome (FRAXA) • Facioscapulohumeral muscular dystroph -- Defects of the methylation machinery • Systemic lupus erythemtosus (SLE) • Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome

Histone Modifications http: //porpax. bio. miami. edu/~cmallery/150/gene/c 7. 19. 4. histone. mod. jpg

Histone Modifications http: //www. nature. com/nsmb/journal/v 14/n 11/images/nsmb 1337 -F 1. gif

Li e. al. (2007) Cell 128, 707

Histone Modifications in Relation to Gene Transcription Li e. al. (2007) Cell 128, 707

Histone Modifications and Human Diseases Coffin-Lowry syndrome is a rare genetic disorder characterized by and abnormalities of the head and mental retardation facial and other areas. It is caused by mutations in the RSK 2 gene (histone phosphorylation) and is inherited as an X-linked dominant genetic trait. Males are usually more severely affected than females. Rubinstein-Taybi syndrome is characterized by short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes. It is caused by mutations in CREB-binding protein (histone acetylation)

RNA Interference (RNAi) http: //www. nature. com/ncpneuro/journal/v 3/n 7/images/ncpneuro 0551 -f 1. jpg

si. RNA Mediated Heterochromatin Maintenance

Technologies for Studying Epigenomics DNA Methylation Microarray or deep sequencing Irizarry et. Al. (2008) Genome Research 18(5): 780

Biosulfite Treatment of Cytosine Treatment of DNA with bisulfite converts cytosine residues to uracil, but leaves 5 -methylcytosine residues unaffected.

Bisulfite Sequencing

Bisulfite Sequencing

Non-methylation-specific PCR based methods

Knowing Difference? Importance of References And Accepting Difference

Genomic T 7 billion persons Genomic Variability 6 billion Bases Genomic Diversity Jong Bhak, under Bio. License

Geno+ Enviro=> Pheno (GEP/T graph) Geno Pheno/Trait Each Trait or Disease Cancer Flu Car accident Enviro the atom of environment Jong Bhak. Under Bio. License: public domain. 36

(Making) Variation is the driving force of the universe Phene Variation Gene Variation Environe Variation Jong Bhak. Under Bio. License: public domain 37

Genome : Envirome : Phenome • Genome = gene types + their variome • Envirome= environe types + their variome • Phenome= phene types + their variome Jong Bhak. Under Bio. License: public domain 38

Prediction is what we do All the algorithms in the world is to predict something Phenome • genome Uncertainty Envirome Jong Bhak. Under Bio. License: public domain ? 39

Complicated • Gene. Complexes Enviro. Comple xes Jong Bhak. Under Bio. License: public domain Phene. Comple xes 40

Structure in Species Genomes Matrix 6 billion people billion Bases x 3(? ) million animal species

Genomic T: Finding Structure in “Population” Matrix 6 billion people 7 billion Bases x 6 billion people Billion Genome Project (Bi. G) http: //billiongenome. com

Geno-Enviro-Pheno Tri. Point Comparative Genomic Sweet Spot Class Population Stratification Polymorphism Functional aberation Genus/Family, …. . Isolation (repro) Speciation, Functionally similar Distant homologs Functionally distinct

Aging and Cancer in a population Phenotypes by variations

The ultimate phenotype • Alive or Dead

Epigenetic Control of Aging • Ursula Muñoz-Najar and John M. Sedivy

Dynamic DNA/chromosome

Methylation pattern DNA methylation age of human tissues and cell types Steve Horvath

Histone and Protein modification