Epigenetics and Disease PDF

EPIGENETICS AND DISEASE Derek Owens DrAP CRNA Module 2 Guyton chapter 3 McCance 4, 5, 6 Learning objectives 1. Describe how genes influence all aspects of body structure and function. 2. Compare how defects in genes can lead to recognizable genetic diseases. McCance chapte...

EPIGENETICS AND DISEASE Derek Owens DrAP CRNA Module 2 Guyton chapter 3 McCance 4, 5, 6 Learning objectives 1. Describe how genes influence all aspects of body structure and function. 2. Compare how defects in genes can lead to recognizable genetic diseases. McCance chapter 6 Epigenetics Modifications that are not included in nucleotide sequence but are never the less transmitted when a somatic cell divides, when gametes are produced, or both Processes that modulate how a given set of genomic information gives rise to phenotype  DNA methylation Plays a prominent role in human health and disease – In females the inactive X chromosome contains large amounts of methylation – The active X chromosome are largely devoid of DNA methylation DNA with dense methylation are not actively transcribed – Epigenetic inactivation of one of the two X chromosomes occurs during gastrulation- a phase of early embryonic development The determination of which chromosome to be silenced, either the copy from the father or from the mother, occurs at random and independently in each cell – Somatic masaicism- differences between the alleles active in two cells can confer two very different traits Due to the random inactivation can arise for any X encoded trait Females who inherit one normal allele and one disease allele at an X encoded gene tend to have less severe disease phenotypes than males who’s lone X chromosome bears a disease allele – Lower severity of color blindness in females  Histone modification Histones are positively charged proteins around which negatively charged DNA molecules are wound Facilitates compaction of DNA into the cellular nuclei – When all the DNA that comprises the human genome is wound around histones it is only 1/40,000th as long – Heterochromatic- when a given segment of DNA is bound tightly to its histones – Euchromatic- when a segment of DNA is only loosely bound to it’s histones When loosely bound transcription factors are able to access it and use it as a template for mRNA production These states of the individual segments of the genome play a critical role in determining the development potential of a given cell Histone modification Histone acetylation- tends to diminish the positive charge of histones reducing the binding strength to DNA Histone methylation can either increase or decrease the bonding strength between DNA and histones depending on the specific parts of the histone they are added Mutations in genes that code histone modifying proteins have been implicated in various pathological states including congenital heart disease – Histone modification is critical to normal development Protamines- evolutionarily derived from histones – Enable sperm DNA to achieve compaction even greater than histone bound DNA – Improves hydrodynamic features and facilitates movement Changes in expression of protomines have been found to be associated with infertility in males (see attached article for further reading if desired) Epigenetics and human development Totipotent- each cell in the early embryo has the potential to give rise to a somatic cell of any type – All of the cells in a given individual contain almost exactly the same genetic information It is the epigenetic information eventually placed “on top of” these sequences that enables them to achieve the diverse functions of differentiated somatic cells Housekeeping genes- a small percentage of genes that are necessary for function and maintenance of cells, they escape epigenetic silencing and remain transcriptionally active in all or nearly all cells  Genomic imprinting Biallelic- both the maternal and paternal inherited copies contribute to offspring phenotype Monoallelic- the maternal copy is randomly chosen for inactivation in some somatic cells in the paternal copy is randomly chosen for inactivation in other somatic cells Imprinting- only about 1% of autosomes, either the maternal copy or the paternal copy is inherited – Genetic conflict hypothesis- although both mother and father benefit genetically from the birth and survival of offspring their interest or not entirely aligned Since mothers make a large physiologic investment in each child it is in their best interest to limit resources given to anyone offspring and maintain capacity to bear subsequent children Except in cases of lifelong monogamy is in the best interest of fathers for their child to exact maximum resources from its mother and limit the mother’s ability to bear additional offspring in the future Imprinted genes from the mother are predicted to limit offspring size whereas in printed genes from the father are predicted to result in larger offspring One important hallmark of imprinting associated diseases is the phenotype is critically dependent on whether the mutation is inherited from the mother or the father Prader Willi and Angelman syndrome Well known diseases of imprinting, they are associated with a deletion of about 4 million base pairs on the long arm of chromosome 15 Prader-Willi syndrome-occurs when this deletion is inherited from the father – Short stature, hypotonia, small hands and feet, obesity, mild to moderate intellectual disability, and hypogonadism Angelman syndrome- is caused by the same deletion inherited from the mother – Severe intellectual disability, seizures, and an ataxic gait Beckwith-Wiedemann syndrome Identifiable at birth because of large size for gestational age, neonatal hypoglycemia, a large tongue, creases on the ear lobe, and omphalocele Have an increased risk of developing Wilms tumor or hepatoblastoma 20 to 30% of cases are caused by inheritance of two copies of chromosome 11 from the father and no copy from the mother – This is called uniparental disomy In contrast the Prader Willie and Angelman syndromes is caused, in part, by over expression of a gene product Russell-Silver syndrome Growth retardation, proportionate short stature, leg length discrepancy, and a small triangular shaped face 1/3 of cases are caused by imprinting abnormalities of chromosome 11p15.5 Another 10% are caused by maternal uniparental disomy  Epigenetics in cognitive development and mental health In utero ethanol exposure – Neural stem cells exposed to ethanol impairs their ability to differentiate to functional neurons Correlates with aberrant, dense methylation at loci that are active in normal neuronal tissue Mental health – Children who grew up in poverty have a typical methylation at a serotonin receptor – PTSD causes alterations in gene expression in key neural pathways that are associated with atypical methylation in a large set of genes Autism spectrum disorder – Associated with alterered DNA methylation at some loci Epigenetics and nutrition During the winter of 1943 people in urban areas of the Netherlands suffered starvation as a result of Nazi blockage of food shipments – Individuals in utero during this time or more likely to suffer from obesity and diabetes as adults – The offspring of those individuals were found to be significantly smaller than children not affected by the blockade  Epigenetics and aging MZ twins exhibit differences in methylation patterns of the DNA sequences of their somatic cells that often result in an increase in numbers of phenotypic differences – Twins with significant lifestyle differences tend to accumulate larger numbers of differences in methylation patterns Mice have exhibited increases in the genome wide abundance of hydroxymethylcytosine with time – Many have proposed that senescence itself can be characterized as an epigenomic phenomenon – Metformin is effective in slowing senescence in yeast Studies have suggested that long-term use of metformin may extend lifespan beyond non-diabetic individuals Metformin may modulate epigenetic pathways with possible opportunities for lifespan extension Epigenetics and cancer Tumor cells often exhibit decreased methylation genome wide relative to normal cells of the same type which can increase the activity of oncogenes Screening for epigenetic misregulation has shown promise as a tool for detecting and characterizing cancer of the colon, breast, and prostate – Other epigenetic based screening approaches have shown promise for bladder, lung, and prostate cancer  Treatment of epigenetic disease Epigenetic modifications are potentially reversible – DNA can be demethylated, histones can be modified to change the transcriptional state of nearby DNA, and microRNA encoding Loci can be up or down regulated – DNA demethylating agents 5-Azacytidine has been used as a therapeutic drug in the treatment of leukemia and myelodysplastic syndrome – Histone deacetylase inhibitors Histone deacetylases increase chromatin compaction causing decreased transcriptional activity Treatment with HDAC inhibitors has shown promise in reducing cell division rates of breast, prostate, and pancreas cancers – miRNA has shown promise for developing drugs that modify only the genes responsible for a specific cancer