12. Epigenetics.pdf

Epigenetics DMED511 Melissa J. MacPherson, PhD, MD, FRCPC, DABMGG, FACMG Medical Geneticist Assistant Professor Department of Medical Genetics University of Alberta September 9, 2024 Objectives Defin...

Epigenetics DMED511 Melissa J. MacPherson, PhD, MD, FRCPC, DABMGG, FACMG Medical Geneticist Assistant Professor Department of Medical Genetics University of Alberta September 9, 2024 Objectives Define epigenetics Describe how epigenetics impacts gene expression Differentiate between somatic changes and germline (inherited) changes Describe the importance of epigenetic changes in human health and disease  Show of hands Who has heard of epigenetics? Who has never heard of epigenetics? Who has heard about DNA methylation and gene regulation? Who has never heard about DNA methylation and gene regulation? Who has taken a genetics course in the past? Who has never taken a genetics course in the past? Epigenetics: Nature vs Nurture https://www.youtube.com/watch?v=k50yMwEOWGU  twins studies in the medical literature show that genetics doesn’t control everything Tzika, E. et al. google search of epigenetics --> hot topic So…what is epigenetics? ? Epigenetic “over” or “above” the genome “both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable” Epigenetic Coined by Conrad Waddington in 1939 Wikipedia.org Wikipedia.org “the branch of biology that studies the causal interactions between genes and their products which bring the phenotype into being” Jean-Baptiste Lamarck (1744-1829), descendants can inherit traits acquired by the habits of their parents and the interactions between individuals and their environments is a key factor in the evolution of species concepts of epigenetics is centuries old How do we develop? how does egg turn to liver, lung, eyes based on which genes are being turned on and off and at what points in development  methyl groups can get attached to the Chemical and Protein Code histone tails to turn on and off genes https://commonfund.nih.gov/epigenomics/figure DNA Methylation cytosine residues in DNA can get methylated and turned off Wikipedia.org Methylation and Gene Expression Wikipedia.org slide to show that this concept is complicated Abcam.com Epigenetic tools: The Writers, The Readers and the Erasers writers, readers, and erasers exist Biswas, S. et al. Villota-Salazar, N. et al. Somatic versus Germline Changes somatic - changes in cells that dont give rise to germ cells germline changes - changes in cells that turn to germ cells and change is passed to offspring A Special Example of Epigenetics: Genomic Imprinting Walters et al.  A Special Example of Epigenetics: X-chromosome inactivation Medical Genetics, 6th edition, Jorde, Carey, females have 2 copies of X chromosone and one X gets silenced —> example of epigenetics Bamshad, 2020, Chapter 5, 73-96. The Role of XIC and XIST Recap There is a protein and chemical code in addition to our nucleotide sequence that plays a key role in regulating the way our genes are turned on and off There is a system of readers, writers and erasers that regulate this process Somatic changes are not passed on to the next generation Germline changes are passed on to the next generation Nature vs nurture, both are important Epigenetics in Human Health and Disease Can anyone think of any examples? cancer biology, famine resistance in population that underwent famine, trauma  Developmental Original of Health and Disease (DOHaD) Harmful exposures that occur early in life, while tissues and organs are developing, may increase the risk of disease later in life Sometimes these risks are carried over into future generations Eg Obesity, Type 2 Diabetes, Asthma, Cardiovascular Disease, Behavioural Disorders, Neurodegenerative Diseases, Some Cancers https://www.niehs.nih.gov/research/supported/health/developmental#:~:text =Studies%20suggest%20that%20harmful%20exposures,health%20and%2 0disease%2C%20or%20DOHaD. Transgenerational Effects in utero, some exposure where it influences the germ line -> exposure in utero can influence subsequent generations Knudsen, T. M. et al. Dutch Famine 1944-1945 – A Classic Example severe starvation over the course of a winter (combination of cold wnter and Nazi) Children wait to be fed during the Dutch Hongerwinter of 1944–1945. S20 | NATURE | VOL 468 | 23/30 December 2010 people conceived during this time were small and underweight this cohort of children had health problems that persistent to their adult lives  Dutch Famine Many children conceived during the Hongerwinter were small and underweight They have also had certain health problems that have persisted long into their adult lives Increased risk for obesity, hypercholesterolemia, hypertension, coronary artery disease, type 2 diabetes, schizophrenia, breast cancer Changes in reproductive function, earlier menopause There is a difference in the methylation profile on their DNA (less methylation of IGF2 gene compared with unexposed siblings) there was an actual difference in DNA methylation at the IGF2 gene Current Opinion in Clinical Nutrition and Metabolic Care: July 2006, Vol 9(4):388-394 when you have high licking rat moms there is differences in DNA methylation in a promoter region in the brain example from YouTube video at the beginning of the slide Addictions and Epigenetics Hamilton, P.J. et al. Curr Opin Neurobiol, 2019:59, 128-136. Ajonijbu, D. et al  dont memorize different drugs of abuse have different epigenetic changes Ajonijbu, D. et al Epimutations in cancer unmethylated - turned on methylated - turned off Esteller et genes can get turned on and turned off in a potentially inappropriate al manner epimutations can drive cells towards cancer Hypermethylation of promoters lots of genes can undergo epigenetic changes in the cancer setting these genes are important for cancer regulation  Epigenetics of Aging Epigenetic clock Changes in CpG methylation across the genome highly correlate with age across tissues Epigenetic age is accelerated by high body mass index and reduced by high levels of education or physical activity, a low body mass index and consumption of fish, poultry , fruits and vegetables  different methylation rates exist in different tissues in the body as chronological age increases our DNA methylation based age Cavalli, G. et al also increases linearly Disruption of the Writers, Readers, and Erasers also results in Epigenetic Alterations  writer - laying down the chemical code on the histones or DNA itself congenital disorder where the writer EHMT1 = Kleefstra causes global gene regulation Disruption of Writers Pathogenic variants or deletions of EHMT1 cause a condition called Kleefstra syndrome Genereviews.org  Intellectual disability, severe speech delay Distinctive facial features Hypotonia Hearing loss Heart and renal defects Severe respiratory infections Epilepsy Autism spectrum disorders almost all have autism Extreme apathy or catatonic like features Psychiatric disorders can get catatonia like symptoms Genereviews.org  MECP2 encodes protein that reads Disruption of Readers methylated cytosine residues Pathogenic variants in MECP2 cause Rett Syndrome  these kids develop normally until age 2ish and then plateau and start to regress Developmental regression hand Partial or complete loss of acquired purposeful had skills Partial or complete loss of acquired spoken language or language skill Gait abnormalities Hand wringing, mouthing disrupting gene thats important for epigenetic Intense eye communication reading of many many genes Inappropriate laughing/screaming spells Growth restriction Abnormal muscle tone Genereviews.org  Imprinting Disorders: Beckwith Wiedemann Syndrome some genes are expressed from mom and silenced from dad and vice versa one case of this is from this disorder the abdominal wall didn’t develop and causes enlarged tongue enlarged organs, one side of the body is bigger than the other patients have increased risk for tumors (liver and kidney are the classic examples) Weksberg et al.  dad’s chromosome we express IGF2 and silence from mom. sometimes we express both and causes excessive growth in the developing embryo Weksberg et al.  Imprinting Disorders: Russell Silver Syndrome Small for gestational age Post-natal growth failure Relative macrocephaly Frontal bossing or prominent forehead Body asymmetry Feeding difficulties Clinodactyly Genereviews.com Smith’s Recognizable Patterns of Human Malformation  cluster of genes on chromosone 11 IGF2 is silenced on both copies leading to slower and smaller growth key message if both genes are turned on, can get excessive growth if both genes are turned off, can get not enough growth Imprinting Disorders: Prader-Willi Syndrome and Angelman Syndrome Prader-Willi Syndrome classic example of imprinting disorder cluster of genes on chromosome 15 deletion from gene that we get from our father starts out with floppy baby - low muscle tone. jello-like and dont feed very well. then they start feeding too much and get obesity and developmental delay. opposite condition is angelman syndrome epigenetic abnormalities can lead to disease Thomspon & Thompson Genetics in Medicine What does the future hold for epigenetics? epigenetic can be targeted for drugs in the future Want to learn more? Questions? [email protected]  References Ahmed, F. Epigenetics: Tales of adversity. Nature 468, S20(2010). https://doi.org/10.1038/468S20a Roseboom, T.J. et al. Hungry in the womb: What are the consequences? Lessons from the Dutch famine. Maturitas, 70(2), Oct 2011, 141-145. Villota-Salazar, N.a. et al. Epigenetics: from the past to the present. Frontiers in Life Science, 2016, Vol 9(4), 437-370. Deans, C. et al. What do you mean, “epigenetic”? Genetics 2015, 199(4), 887-896. Biswas, S. et al. Epigenetic tools (The writers, the readers and the erasers) and their implications in cancer therapy. Euro J of Pharmacology Oct 15, 2019, 837, 8-24. Tzika, E. et al. Epigenetics and Metabolism in Health and Disease. Front. Genet, 18 Sept 2018. https://doi.org/10.3389/fgene.2018.00361 Walter, J. et al. Imprinting and disease. Seminars in Cell & Developmental Biology 14(2003) 101-110. Knudsen, T. M. et al. Transgenerational and intergenerational epigenetic inheritance in allergic diseases. J Allergy and Clinicla Immunology, 142(3), 765-772. Jorde, Carey, Bamshad. Medical Genetics, 6th edition, 2020, Chapter 5, 73-96.  exam classic examples of where epigenetics can lead to human disease M. Esteller. Cancer epigenomics: DNA methylomes and histone- modification maps. Nature Reviews Genetics, 2007, 8, 286-298. Weksberg, R. et al. Beckwith-Wiedemann Syndrome. Eur J Hum Genet (2010) 18, 8-14. Eggermann, T. et al. Silver-Russell syndrome: genetic basis and molecular genetic testing. Orphanet Journal of Rare Diseases 2010, 5:19. Nussbaum, R.L. et al. The chromosomal and genomic basis of disease: disorders of the autosomes and sex chromosomes. Chapter in Thompson & Thompson Genetics in Medicine, 8th edition, 2016. Elsevier Inc. Hamilton, P.J. et al. Epigenetics and Addiction. Curr Opin Neurobiol (2019), 59: 128-136.