HSS2305A - 2024 Lecture 11 and 12 PDF

HSS2305: Molecular Mechanisms of Disease Lecture 11 and 12 – Gene-Environment Interactions - Epigenetics Spring 2022 Prof. Keir Menzies Today’s Outline Announcements Assignments Sample Questions Welcome back...

HSS2305: Molecular Mechanisms of Disease Lecture 11 and 12 – Gene-Environment Interactions - Epigenetics Spring 2022 Prof. Keir Menzies Today’s Outline Announcements Assignments Sample Questions Welcome back the next half of Control of Gene Expression the course! Announcement - Assignment Deadline Tuesday. Reminder: NO PLAGIARISM Assignment - References In Text Citations Indicate which statements/facts in your main text (i.e. summary/abstract) come from which reference in your references/bibliography section Ex. Bibliography Contains list of sources for facts used in main text Ex. Assignment - Figures Ex. Instructions for Assignment Submission For this assignment, you are required to submit your work as either a Word or PDF document. Please carefully follow the instructions below for naming your file before submission: File Naming Format: #. DiseaseName_StudentName.pdf Replace # with the number corresponding to the disease you've selected from the list below. Replace DiseaseName with the name of your selected disease. Replace StudentName with your full name (e.g., JaneSmith). Example: If you choose Cystic Fibrosis and your name is Jane Smith, your file name should be: 7. CysticFibrosis_JaneSmith.pdf List of Rare Diseases: 1.Alkaptonuria 2.Amyloidosis 3.Cerebral Palsy 4.Crohn’s Disease 5.Creutzfeldt Jakob Disease 6.Cushing Syndrome 7.Cystic Fibrosis 8.Duchenne Muscular Dystrophy 9.Legionnaires’ Disease 10.Mesothelioma 11.Prader-Willi Syndrome 12.Tourette Syndrome 13.Syphilis 14.Ulcerative Colitis 15.Wilson Disease 16.Yellow Fever C riteri a Non e/Ab sent Insu fficien t Fa ir Goo d Ex celle nt Criterio n Sco re History and background of the disease 0 points 1 point 2 points 3 points 4 points Score of History and background of Student did not provided any information Student provided some accurate information about Student provided some accurate information Student provided some accurate information Student accurately provided information about all the disease, about the history and background of the the history and background of the disease, about the history and background of the about the history and background of the of the following points: /4 disease addressing only one of the main points related to disease, addressing only two of the main disease, addressing three of the main points How and when the disease first originated/was OR the history and background of the disease. points related to the history and background related to the history and background of the discovered Student provided a significant number of of the disease. disease. Discussed the history of the disease inaccurate information about the history and Discussed the global statistics of the disease background of the disease Discussed why the disease is considered rare Disease pathology 0 points 1 point 2 points 3 points 4 points Score of Disease pathology, Student did not provided any information Student provided limited or inaccurate information Student provided some accurate information Student provided mostly accurate information Student accurately provided information about all / 4 about the disease pathology about the disease pathology. Only basic symptoms about the disease pathology, however key on the disease pathology, including type, of the following points: OR were mentioned without discussing the disease's elements such as the type, cause, or symptoms, and possible causes, however, the Discussed the characteristics of the disease, its underlying pathophysiology, type, or potential comprehensive details of the disease were explanation lacked depth or missed some key type, pathophysiology, symptoms, characteristic consequences. missing or not fully explained. characteristic. features, consequences, fatality, etc. Discussed the possible cause of the disease using a Figure, Scheme or a Pathway diagram (drawn by you) to support your point. Figure / Scheme 0 points 1 point 2 points 3 points 4 points Score of Figure / Scheme, Student did not provide a figure or scheme Student provided a figure or scheme which was Student provided a basic figure or scheme, Student provided a figure or scheme which was Student accurately : /4 OR either incomplete or inaccurate, or the figure was however, it lacked clarity or detailed steps of mostly accurate, illustrating important pathways Drew a schematic diagram of pathways or Student did not provide an original figure copied from another source. the disease mechanism. Some key processes or steps of the disease progression. However, biochemical steps highlighting the disease (figure was copied from another source) were missing or not well represented. some details or labels were unclear, or the initiation/progression/mechanism. figure could have been more comprehensive. Submitted an original figure or diagram they created (not copied from another source). Treatment/Prevention/ Limitations/side effects 0 points 1 point 1 point 3 points 4 points Score of Treatment/Prevention/ and efficacy of the treatment. Student did not provided any information Student provided only minimal or general Student provided some information about Student accurately discussed available Student accurately: Limitations/side effects and efficacy about the treatment, prevention, limitations, information about the treatment options, without available treatments and touched on their treatments and their efficacy, however, the Discussed potential/available treatments. of the treatment., side effects, or the efficacy of the treatment addressing limitations, side effects, or efficacy. The effectiveness, however, the discussion of side explanation of limitations or side effects was Discussed the effectiveness of the treatment. /4 explanation lacked depth and relevance. effects, limitations, and relevant factors, for somewhat limited or lacked in-depth analysis of Discussed the limitations, side effects, and any example age or gender was incomplete. certain factors, for example age or gender. gender-, age-related factors, etc. References/Bibliography 0 points 0.5 points 1 point 1.5 points 2 points Score of References/Bibliography, Student did not include any references There are from one to three peer-reviewed There are from four to six peer-reviewed There are from seven to nine peer-reviewed Student included /2 OR references references references Included 10 to 15 references (maximum of 15) Student provided a reference/bibliography AND/OR AND/OR AND/OR including patents if used. section which include a significant number of Many references are not peer-reviewed Some references are not peer-reviewed A few references are not peer-reviewed References are peer-reviewed. errors AND/OR AND/OR AND/OR Followed APA formatting. AND/ OR References are incorrectly cited within the text References are incorrectly cited within the References are incorrectly cited within the text References were from within the last 10 years A significant number of errors in the citations AND/OR text AND/OR (from 2014 until present). within the text References are cited incorrectly in the reference AND/OR References are cited incorrectly in the reference AND/OR section References are cited incorrectly in the section References are not from within the last 10 AND/OR reference section AND/OR years References are not from within the last 10 years AND/OR References are not from within the last 10 years References are not from within the last 10 years Overall write up style 0 points 0.5 points 1 point 1.5 points 2 points Score of Overall write up style, Assignment was not well organized and is Assignment has several organizational issues or is Assignment has some organizational issues or Assignment has a few organizational issues or is Assignment: /2 unclear. There was a significant number of somewhat unclear. There are several spelling is somewhat unclear. There are some spelling a bit unclear. There are a few spelling errors. Flowed/ was logical, organized, well written, used spelling errors. errors. errors. AND/OR appropriate wording, correct spelling, and AND/OR AND/OR AND/OR The one page (Letter, 8.5 x 11 inches) limit was grammar. The one page limit was surpassed or The one page (Letter, 8.5 x 11 inches) limit was The one page (Letter, 8.5 x 11 inches) limit surpassed Limited to one-page (Letter, 8.5 x 11 inches), document was less than half a page in length surpassed or document was between half a page was surpassed or document was between AND/OR singled spaced (not including diagram) AND/OR and 3/4 of a page in length and 3/4 of a page and on page in length The 1 inch margin was not respected Had 1 inch margin on all sides of the paper The 1 inch margin was not respected AND/OR AND/OR AND/OR Font used was Times New Roman or Arial font AND/OR The 1 inch margin was not respected The 1 inch margin was not respected Did not use Times New Roman or Arial size 11 Font Size was 11 Did not use Times New Roman or Arial size 11 AND/OR AND/OR font Single spaced font Did not use Times New Roman or Arial size 11 font Did not use Times New Roman or Arial size 11 AND/OR Used headings and subheadings AND/OR AND/OR font Document was not single spaced Document was not single spaced Document was not single spaced AND/OR AND/OR AND/OR Document was not single spaced Did not use headings and subheadings Did not use headings and subheadings AND/OR Did not use headings and subheadings Lecture 11 Review Questions 1. Co-activators do not: a) Enhance gene expression b) Bind directly to DNA c) Bind to PIC d) Interact with histones 2. The iron regulatory protein (IRP): a) Prevents Ferritin mRNA translation b) Binds Iron when Iron levels are high c) is an example of translational modification d) All of the above 3. RNA interference is not mediated by: a) Histones b) siRNA c) miRNA d) Dicer 4. What is the structure that degrades peptides? a) Polysome b) Proteosome c) Ribosome d) PIC Questions from Last Lecture? REGULATION OF GENE EXPRESSION NATURE-NURTURE DEBATE Our genetic Our lifestyle make up choices (inheritance) (environment) dictates dictate health health and and disease disease Nature vs. Nurture NATURE-NURTURE DEBATE Our genetic Our lifestyle make up choices (inheritance) EPIGENETICS (environment) dictates dictate health health and and disease disease Nature vs. Nurture GENETICS REVIEW Heredity = passing of traits to offspring DNA PACKAGING Chromosome organized structure of DNA and associated proteins Mb: millions of base pairs or mega base Pack age large amounts of DNA into a small space pairs = 1,000,000 (human nDNA is 3,200 Mb Contains a single, continuous piece of DNA or 3 200 000 000 nucleotides of DNA) Diploid Cell Human diploid cell Contains pairs of chromosomes Contains 23 pairs of chromosomes 46 chromatids in total 22 pairs of autosomal chromosomes 1 pair of sex chromosomes Each chromosome in a diploid cell comes as a homologous pair (one chromatid from mom, one from dad =23 pairs or 46 chromatids). When a cell prepares to divide, each chromosome replicates, creating two identical copies, called sister chromatids, for each original chromosome – so now 46 pairs of sister chromatids. These sister chromatids are connected at a region called the centromere. During mitosis, the sister chromatids are separated into the daughter cells, each of which will end up with 46 chromosomes (23 pairs) again, each as a single chromatid. Haploid cells Contain 23 unpaired chromosomes (i.e. an unpaired chromatid that is from one parent only) Result of meiosis Ex. gametes: spermatozoa (sperm) and oocytes Humans: 23 chromosomes total 23 chromatids  DNA PACKAGING HISTONES Chromatin DNA + associated proteins Histone Proteins that packages DNA Octamer – 8 proteins Positively charged Interacts with negative charged DNA ”Histone Tails” N-terminus Modified by key enzymes Affects histone charge, DNA compaction and gene transcription Nucleosome Individual complex of histone proteins and supercoiled DNA 146 bp of DNA wrapped (almost twice H2A , H2B , H3 and H4 (1.65x)) around histone core Luger er al., Nature 1997 2X of each H2A, H2B, H3, H4  DNA PACKAGING HISTONES Packaging ratio of 10,000:1 Chromosomes: 23 pairs Nucleosome: DNA + histone octomer Chromatin: Euchromatin DNA + associated Heterochromatin proteins (histones, transcription proteins etc.) https://www.dnalc.org/view/15482-DNA- packaging-3D-animation-with-advanced- DNA: narration-and-labels.html 4 base pairs (A,T,G,C) Encode genes  Chromatin is DNA PACKAGING densely packed and HISTONES found in Chromatin is less heterochromatin compact and more (inactive areas of accessible the chromatin) H1 - linker histone Not involved in octamer Binds to linker DNA and connects nucleosomes Nucleosome HISTONES AND GENE EXPRESSION Non-genetic modifications to histones - profound impact on what genes are transcribed How?  HISTONE MODIFICATIONS Histone code hypothesis Activity of a chromatin region depends on the degree of chemical modification of histone tails docking sites to recruit non-histone proteins alter interactions of neighboring nucleosomes K - Lysine R - Arginine S - Serine T - Threonine Lawrence et al. , Trends in Genetics 2016  Introduction to Epigenetics https://www.pbslearningmedia.org/resource/biot09.sci.life.gen.epigenetics/epigenetics/#.YD_4 WHAT IS EPIGENETICS? Epigenetics study of heritable changes in gene expression or phenotype caused by mechanisms other than changes in underlying DNA sequence Coined by CH Waddington in 1942 Functionally relevant modifications to the genome that do not involve a change in nucleotide sequence Turn genes on (activate) or off (silence) Potentiate or inhibit gene expression Epigenome Overall epigenetic state of a cell Epigenetics can be highly preserved Even with: Cell Division (Mitosis) Preserved for lifetime but can also change over a lifetime Germ Cells (Meiosis) Transferred to next generation Means by which genetic material responds to changing environmental conditions WHAT IS EPIGENETICS? What causes these epigenetic changes? Nature Inheritance Normal development Environmental influences (Nurture) Diet Exercise Stress Toxins Biochemistry/physiology (i.e. hormones) Epigenetic landscape: Conrad Waddington(1905–1975) Time 0 Time 1 Time 2 Time 3 Conrad Waddington Germ Mesoderm Endoderm Ectoderm Cells NCBI WHAT IS EPIGENETICS? Epigenetic marks Gene X Gene Y Gene Z WHAT IS EPIGENETICS? Gene X Gene Y Gene Z Gene silencing WHAT IS EPIGENETICS? Gene X Gene Y Gene Z Gene activation WHAT IS EPIGENETICS? G A B C D G A B C D Critical to morphogenesis: the process of shaping an organism's G A B C D structure, guiding the formation and organization of tissues and organs to create its overall form Can Epigenetics be reprogrammed? G A B C D *Oct 4, Klf4, Sox2, c-Myc Yamanaka factors: can reprogram the epigenome to convert somatic cells into induced pluripotent stem cells (similar to the cells in the blastocyst- the ball rolling down the Waddington’s epigenetic landscape) G A B C D G A B C D Critical to morphogenesis WHAT IS THE PROOF that our environment can alter epigenetics and affect expression of genes? Agouti mouse model: Genetically identical mice Agouti gene activated – yellow fur coat, obesity silenced – brown fur coat, normal weight Modulate expression of the agouti gene in offspring through enrichment of maternal diet with methyl rich supplements (i.e folic acid) to silence the Agouti gene Agouti gene agouti gene through DNA activated silenced methylation (not histone tails but still epigenetics) Genetically identical mice FASEB J. 1998; 12: 949-957. WHAT IS THE PROOF ? Twin Studies: Monozygotic (identical) twins identical genetic make-up at birth and death Across a lifespan they can differ significantly in environmental exposures Share a genome but not an epigenome, not necessarily destined to share the same fate Differences in health and disease Cancer Diabetes Cardiovascular disease Asthma Differences become more apparent over time - longer exposure time WHAT IS THE PROOF? Twin Studies: Research on 80 sets of identical twins DNA is marked in different ways by methylation over time Much more pronounced in older twins Proc Natl Acad Sci U S A. 2005; 102(30):10604–10609. MECHANISMS OF EPIGENETICS i.e. Some lncRNAs can help 3 alter the structure of chromatin in a way that can either activate or silence genes (coming up soon) 2 1 MECHANISMS OF EPIGENETICS 1. DNA METHYLATION (New England Biolabs) MECHANISMS OF EPIGENETICS 1. DNA METHYLATION RNA polymerase Gene activation CGCGCGCGCGCGCG GCGCGCGCGCGCGC CpG island RNA polymerase DNMTs Gene silencing Me Me CGCGCGCGCGCGCG GCGCGCGCGCGCGC CpG island DNA methyltransferases (DNMTs) can methylate CpG islands MECHANISMS OF EPIGENETICS 1. DNA METHYLATION No methylation of CpG – gene “on” Tissue specific genes, housekeeping genes Methylation of CpG – gene “off” Genes not specific to that tissue, silent DNA Methylation of CpG’s done through DNA methyltransferases (DNMTs) Knock it out – lethal in animals (early in development) Over-express – cancers in humans if too much DNMTs then genes responsible for transitioning from a blood stem cell are not turned on at the right time, resulting in an accumulation of blood stem cells that can lead to leukemia) Methyl groups acquired through diet methionine (provides the methyl group), selenium and folate are required for transferring the methyl group Incorporation of methyl groups can be influenced by environmental toxins (I.e Bishpenol A – used to be in lots of water bottles or plastics that are not dishwasher safe or can leach into our environment) MECHANISMS OF EPIGENETICS 1. DNA METHYLATION Methylation pattern maintained through cell replication (mitosis) Me Me DNMT1 TCGA TCGA AGCT AGCT Me Me TCGA Replication Methylation AGCT Me Me TCGA TCGA AGCT AGCT DNMT1 Me Me  MECHANISMS OF EPIGENETICS 2. HISTONE MODIFICATION (New England Biolabs - https://www.youtube.com/watch?v=nygyUMODV7Y MECHANISMS OF EPIGENETICS 2. HISTONE MODIFICATION Methylation of Histones: Addition of methyl groups to lysine or arginine residues on histone tails Sometimes a marker for gene silencing I.e. Methylation of lysine 9 on Histone 3 H3 Sometimes a marker of gene activation K9 H3 I.e. Methylation lysine 4 on Histone 3 Me Methylation of histones done through histone methyltransferases (HMTs/KMTs) Reversed by lysine demethylases (KDMs) Me and Jumonji C (JmjC) domain-containing K4 demethylases H3 H3 Can also influence DNA methylation patterns  MECHANISMS OF EPIGENETICS 2. HISTONE MODIFICATION Acetylation of Histones: H3 H3 HATs Acetyl- H3 RNA H3 polymerase Gene activation Histone acetyltransferases (HAT/KAT) Acetyl- RNA HDACs polymerase H3 H3 Histone deacetyltransferases (HDAC/KDAC) Gene silencing MECHANISMS OF EPIGENETICS 2. HISTONE MODIFICATION Acetylation of Histones: Acetylation of lysine residues on histone tails Removes positive charge of histone tail Loosens the histone-DNA complex Acetyl-CoA is donor for Acetyl groups Marker of gene activation Histone acetyltransferases (HAT/KAT) Adds acetyl groups Histone deacetyltransferases (HDAC/KDAC) Removes acetyl groups Activity of these enzymes can be regulated by several environmental factors Can change rapidly within a cell cycle MECHANISMS OF EPIGENETICS 3. LONG NONCODING RNAS  MECHANISMS OF EPIGENETICS 3. LONG NONCODING RNAS Long non-coding RNA (lncRNA): sequence-specific molecules can guide protein complexes to specific sites in the chromatin and orchestrate transcriptional repression- here is an example: transcriptionally active epigenetic mark HOX Transcript AntIsense RNA transcriptionally repressive epigenetic mark Chr 12 Chr 2 lncRNA HOTAIR is being transcribed from a portion of the HOXC locus located in human chromosome 12 ESTABLISHMENT OF THE EPIGENOME Epigenetic reprogramming Erasure and remodeling of epigenetic marks Two crucial developmental stages in which the epigenome undergoes profound reprogramming 1. Gametogenesis (production of gametes - sperm and oocytes [eggs] via meiosis) Imprint erasure X-chromosome reactivation (females only) Imprinting 2. Pre-implantation (key developmental steps before the embryo implants in the uterine wall) De-methylation X-chromosome inactivation (females only) Tissue-specific methylation (morphogenesis)  ESTABLISHMENT OF THE No more gametogenesis for Paris EPIGENOME Gametogenesis: Formation of gametes (sperm and oocytes) Sperm Oocytes Epigenome Imprint erasure Parental imprinting Epigenetic that resembles (sex-specific) modifications a somatic cell (environmental influences) X chromosome reactivation in females ESTABLISHMENT OF THE EPIGENOME Imprinting: Gene expression occurring from 1 allele only - parent- of-origin-specific manner parents contribute equally to genetic content, however imprinted genes not equally expressed I.e. gene located at a maternally imprinted locus Gene from mother turned "off“ Gene from father turned “on” Activation and silencing due to epigenetic modifications DNA methylation, histone modification Occurs in < 1 % of all genes (~ 80 genes) involved in: Embryonic and placental development Growth and metabolism ESTABLISHMENT OF THE EPIGENOME Imprinting: Established in germ line and maintained in somatic cells 1. Erasure 2. Imprint established according to the sex of the individual; i.e. sperm - paternal imprint 3. Imprint is maintained during fertilization and pre- implantation 4. Imprint is maintained in somatic cells (non- reproductive cells) for a lifetime Imprinted genes are especially sensitive to environmental signals single active copy = no back-up Environmental signals can also affect the imprinting process itself, impacting gene expression in next generation diet, hormones, toxins ESTABLISHMENT OF THE EPIGENOME Imprinting: Established in germ line and maintained in somatic cells 1. Erasure 2. Imprint established according to the sex of the individual; i.e. sperm - paternal imprint 3. Imprint is maintained during fertilization and pre- implantation 4. Imprint is maintained in somatic cells (non- reproductive cells) for a lifetime Imprinted genes are especially sensitive to environmental signals single active copy = no back-up Environmental signals can also affect the imprinting process itself, impacting gene expression in next generation diet, hormones, toxins ESTABLISHMENT OF THE EPIGENOME Imprinting: Established in germ line and maintained in somatic cells 1. Erasure 2. Imprint established according to the sex of the individual; i.e. sperm - paternal imprint 3. Imprint is maintained during fertilization and pre- implantation 4. Imprint is maintained in somatic cells (non- reproductive cells) for a lifetime Imprinted genes are especially sensitive to environmental signals single active copy = no back-up Environmental signals can also affect the imprinting process itself, impacting gene expression in next generation diet, hormones, toxins ESTABLISHMENT OF THE EPIGENOME Pre-implantation: Post-fertilization (an oocyte is fertilized and becomes a zygote) The developing embryo moves from oviduct (fallopian tube) to the uterus Develop into blastocysts Blastocysts forms and implants into the uterus Fertilization Zygote 2 cells 4 cells 8 cells Morula Blastocyst Fetal Development Genome wide demethylation Genome wide, tissue specific methylation and histone *Exceptions: imprinted modification patterns emerge genes, some non-imprinted genes X chromosome inactivation in females ESTABLISHMENT OF THE EPIGENOME X chromosome inactivation in females: one copy of X chromosome is inactivated by epigenetic modification in female offspring only want 1 copy of X chromosome gene products (like males) X chromosome selection for silencing is random in each cell Mediated via lncRNA Will remain silenced across lifespan ESTABLISHMENT OF THE EPIGENOME X chromosome inactivation: TSIX - Blocking protein (or BP) protects one X chromosome from being target for epigenetic modification XIST - Long non-coding RNA coats the other X chromosome that will be silenced Active X chromosome Inactive X chromosome BP X chromosome Long non- inactivated XIC* DNMTs coding RNA Note: ~ 25% of human genes on the X chromosome escape inactivation – copies of these genes are also on Y chromosome *X inactivation center (XIC)  EPIGENETICS ACROSS A LIFETIME Life Span Genome Epigenome Uterine Parental care/ Family Work environment attachment Friends Stress Environment Infections Stress School Relationships Maternal Nutrition Lifestyle Lifestyle behavior Infection choices choices Health and Disease EPIGENETICS ACROSS A LIFETIME (2012) High fat diet (overfeeding) (HFD) associated with: Metabolic disturbances and obesity Cardiovascular disease Cancer HFD for 5 days, collection of skeletal muscle biopsies HFD introduced widespread DNA methylation changes affecting 45% of studied genes (6,508 genes) inflammation, reproductive system, cancer Methylation changes were only partly reversed after 6-8 weeks EPIGENETICS ACROSS A LIFETIME Prenatal smoke exposure associated with: reduced birth weight poor developmental and psychological outcomes risk for diseases and behavioral disorders later in life Global and gene specific differences in CpG DNA methylation patterns associated with in utero exposure to maternal smoking Genes related to cancer progression and immune response EPIGENETICS ACROSS A LIFETIME Adversity/stress in childhood associated with: Psychiatric disorders (depression, anxiety) Drug and alcohol abuse Animal models with low levels of maternal care Disruption/lack of adequate nurturing (parental loss, childhood maltreatment, and poor parental care) - increased CpG methylation of the glucocorticoid receptor gene (responds to stress) exaggerated hormonal and behavioral responses to stress EPIGENETICS ACROSS A LIFETIME Age associated with increased DNA methylation However Exercise training results in methylome of muscle tissue of aged humans transitioning towards that seen in young adults History of training results in more responsive transitions of old muscle methylome towards young EPIGENETICS ACROSS A LIFETIME Folic acid supplementation results in DNA methylation changes Changes (increases) found at developmental and cancer associated genes Epigenetic effects of a lifetime may be counteracted Differences were modest about 5% (25% differences between youth and elderly) EPIGENETICS AND DISEASE CANCER Most cancers have adult onset Genome is static from birth (except for mutations), epigenome is not. Many cancers involve DNA mutations and epigenetic changes Role for epigenetics in the etiology of cancer Mechanisms of epigenetic modification in cancer 1. DNA methylation Hyper vs. hypo-methylation 2. Histone Modification Methylation and acetylation 3. Disruption of the epigenetic machinery DNMTs, HDACs 4. Loss of imprinting IGF-2 - Wilms Tumor (IGF-2 is a growth factor, if not imprinted on one chromosome then too much expression and signal for cell growth) EPIGENETICS AND DISEASE CANCER 1. DNA methylation Hyper-methylation - tumor suppressor genes (TSG) and repair genes Hypo-methylation - oncogenes Methylation balance is KEY! EPIGENETICS AND DISEASE CANCER 1. DNA methylation Hyper-methylation - tumor suppressor genes (TSG) and repair genes TSGs - Inhibit cell division and growth Hypo-methylation - oncogenes Oncogenes - Methylation balance is KEY! Promote cell division and growth EPIGENETICS AND DISEASE CANCER 2. Histone modification histone methylation and de-acetylation (deactivates) gene expression Nature Reviews Genetics. 2007;8:286-298 Silencing of tumor suppressor genes EPIGENETICS AND DISEASE CANCER 3. Disrupted Epigenetic machinery (DNMTs) (HATs) (HDACs) Nature Reviews Genetics. 2007;8:286-298 EPIGENETICS AND DISEASE CANCER 4. Loss of Imprinting (LOI) Bi-allelic expression of a normally imprinted gene 2 X amount of gene expressed Ex. Wilms tumor ▪ Controlled cell growth and ▪ Overgrowth, inhibition of death apoptosis ▪ Cancerous tumor EPIGENETICS AND DISEASE CANCER 4. Loss of Imprinting (LOI) Bi-allelic expression of a normally imprinted gene 2 X amount of gene expressed Ex. Wilms tumor ▪ Controlled cell growth and ▪ Overgrowth, inhibition of death apoptosis ▪ Cancerous tumor EPIGENETICS AND DISEASE CANCER Cancer therapy and epigenetics: Epigenetic profiles for screening Epigenetic profiles for prognosis Pharmacological targeting of epigenetic machinery DNMT inhibitors (Azacitidine, Decitabine) HDAC inhibitors (Vorinostat, Romidepsin) Next Lecture DNA Replication, DNA Damage and DNA Repair