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Epigenetics of Autism Spectrum Disorder.

Epigenetics of Autism Spectrum Disorder.

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  • GOD IS IN CONTROL!!!
  • Daughter cells-offspring Heritable modifications in gene function
  • Epigenetic factors, the chemical markers that attach to genes and affect how they are expressed Epigenome silences the unneeded ones to make cells different from one another. Epigenetic patterns reset when organisms reproduce, but some epigenetic markers can be inherited. Inheritance is more than just your gene sequence. Genes not only thing that passes down from generation to generation
  • All play role in regulation of gene expression
  • Watson and Crick discovered structure of DNA
  • DNA wraps around histones make protein-DNA complex called chromatin Small beads known as nucleosomes Within chromosome, DNA packaged into chromatin Histones: maintain chromosome shape and structure
  • Example of how genes can be directed by environment Regulates chromosomal stability and gene expression CpG islands-site of promoter. If methylated at these sites then no transcription. DNA is not expressed. DNA is methylated by methyltransferase enzymes on cytosine nucleotides. Can be removed. They are inherited unlike histone modifications. Involved with the differentiation of cells Associated with imprinting, X-chromosome inactivation
  • Expression of gene so proteins are made Deacetylation causes DNA to become tightly wrapped around the histone to were the gene cannot be expressed
  • Rich in methyl groups Proof how environment can impact epigenome resulting in different phenotypes Agouti gene affects their fur color, weight, and propensity to develop cancer. Pregnant mothers are yellow, offspring our brown The brown color was inherited by next generation of mice until toxin was introduced in diet which turned them yellow.
  • First epigenetic inheritance found in humans. Environmental info was being imprinted on the egg and sperm at time of their formation. What your grandmother was exposed to when she was pregnant can cause a disease in you even though you never had exposure and you will pass it down to your greatgrandchildren. Studied connection between poor nutrition and health
  • Children exposed to famine later on in preg have no change to their DNA IGF2:Insulin-like growth factor protein-promotes growth and division of cells An environmental exposure you grandmother had can cause a disease in you even though you have never been exposed to toxin, and you will pass it on to great grandchildren. So a mother’s diet only during early pregnancy affects the way in which her embryo’s DNA is methylated.
  • De novo(mutation that neither parent possessed nor transmitted) hypermethylation of promoter CpG islands may lead to silencing of tumor suppressor genes and DNA repair genes Silencing of critical genes that turn normal cells to cancer cells Methylation caused by chemicals Key to therapy is to stay away from killing cell Harder to fix damaged genes than to rearrange epigenetic tags
  • During fright/flight response, cortisol is released Rats who have GR protein relax quickly after stress Rats with little GR protein remain stress much longer
  • heritability explains more than 90% of the risk of autism Younger twins who spent more years together/ shared similar lifestyles had same DNA methylation pattern Older twins who spent fewer years together/different lifestyles had different patterns in different tissues MZ-identical DZ-fraternal Classic autism MZ 60 DZ 0 Broader autistic phenotype that included communication and social disorders: look on slide Disparity between MZ twins could be caused by epigenetic factors Monozygous twins share a common genotype. However, most monozygotic twin pairs are not identical; several types of phenotypic discordance may be observed, such as differences in susceptibilities to disease and a wide range of anthropomorphic features. The specific changes that Dr. Dumanski and his colleagues identified are known as copy number variations, in which a gene exists in multiple copies, or a set of coding letters in DNA is missing. Not known, however, is whether these changes in identical twins occur at the embryonic level, as the twins age or both.
  • Asperger disorder, PDD ASD associated with several genetic disorders Learn about disorders which are genetic disorders which affect known epigenetic pathways to learn what’s going on in autism
  • ASD: multiple genetic and nongenetic causes Help to find candidate genes Find genes that may work in concert/that overlap with each other that have different features to make up those related to autism Cormmorbity with other disorders Common link is that the brain is always affected Higher risk for ASD Boys Siblings of those with autism People with certain other developmental disorders, such as Fragile X syndrome
  • 1-44 are autosomal
  • Single known genetic cause along with Fragile X MECP2 encodes known epigenetic factor MeCP2 protein Involves key epigenetic regulatory factor and X-inactivation since X-linked X-linked meaning that gene causing disorder is on X chromosome Rett syndrome is usually caused (95% or more) by a de novo mutation in the child (so it is NOT inherited from either parent, neither parent possessed nor transmitted. Parents are generally genotypically normal, i.e. one without a MECP2 mutation). Mutated gene derived from male copy of X chromosome
  • Involves x-inactivation Severe in boys because they get only X-chromosome from mother
  • AS: loss of maternal contribution/If copy doesn’t have maternal imprinting then AS PWS: loss of paternal contribution/If copy doesn’t have paternal imprinting, then PWS If copy doesn’t have maternal imprinting then AS Genomic imprinting-PWS: activities of genes in maternal chromosome are repressed (through methlytion) as a result of GI. Patenal chromosome necessary for normal development. Deletion of several genes in the region of 15q11-q13 UPD (Uni-parental disomy of chromosome 15q11-q13 UPD-AS: xtra paternal UPD-PWS: xtra maternal All deletions and UPD are de novo events (neither parent possessed nor transmitted) Both imprinting needed for normal development
  • These two MBD proteins may share some functional overlap in the regulation of social interaction, anxiety, depression and learning. MECP2/Mecp2 deficiency causes reduced expression of UBE3A/Ube3a as well as GABARB3/Gabarb3.
  • Candidate gene Finding connection/common denominator Autism and Rett share several phenotypic features: loss of social and language skills, gain in repetitive stereotyped behavior Evidence in overlap are: MeCP2 expression is significantly reduced in 79% of autism post-mortem brain samples•Methylation of the MECP2 promoter correlates with reduced expression in male autism brain samples•GABRB3 expression (15q11-13) is significantly reduced in 56% of autism post-mortem brain samples•Biallelicexpression levels of GABRB3 are epigenetically dysregulatedin Rettand autism postmortem brain•Homologous pairing of 15q11-13 in mature neurons is deficient in RTT, autism, and AS
  • The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits. Depression: maybe because of the use of anti-depressant drugs in autism Joint attention Social communication Reciprocal social interactions Language delay
  • Found mutation in MBD1 gene The mechanism by which Mbd1 mutations lead to autistic behaviors in mice is not well understood, but finding mice with this phenotype opens the door for understanding how these different cognitive pathways are regulated
  • Mbd1-/- lack of protein
  • Prepulse stimulus acts to suppress the response to a strong startle stimulus PPI-sensorimotor gating process sensorimotor gating" refers to the state-dependent regulation of transmission of sensory information to a motor system. Floating, kicking and twitching behaviors are all said to be depression like behaviors Swimming, climbing thrashing behaviors are all considered to be escape directed behaviors
  • Have reduced PPI which may account for inability to inhibit repetitive thoughts and actions PPI deficit not due to input or hearing based on baseline results
  • Lack of receptor sites able to receive serotonin that is made Mbd1 as a key regulator of this receptor not levels of serotonin Providing explanation of link between Mbd1 and autism-like behavior
  • Hippocampus associated with learning, memory and emotions Work has just begun but the hope is that by finding identical genes that differ in their expression, some causes of autism may emerge.
  • Influced by environmental factors SHANK3 gene has been reported to be altered in individuals with autism.
  • BPA-looking to see if exposures can induce epigenetic modifications. Lack of Vitamin D in mother and children Other studies, go to autism speaks website

Autism Ppt1 Autism Ppt1 Presentation Transcript

  • Epigenetics of Autism Spectrum Disorder Chinyelu Mozie University of Texas at Dallas March 25, 2009
  • What is Epigenetics
    • Weinhold:
    • “ any process that alters gene activity without changing the DNA sequence, and leads to modifications that can be transmitted to daughter cells” (p. 163).
  • What is epigenetics
    • Means above the genome
    • Born with epigenome
      • All cells have same genes
      • Tells our cells what sort of cells they should be-cell differentiation
        • skin, heart, hair, liver, etc
    • Regulating gene function
      • Affect the way we produce proteins
    • Can be transgenerational
      • Contains heritable epigenetic information
    • Interaction with gene and environment
  • What is epigenetics
    • Does not only occur in utero but throughout life span
    • Conrad Waddington credited for term epigenetics in 1942
      • Increase of usage of word in 1990’s
  • Epigenetic Processes
    • Gene silencing
    • X-chromosome inactivation
    • Imprinting
  • Mechanisms
    • DNA Methylation
      • addition of methyl groups to DNA at CpG sites
    • Chromatin/Histone modifications
      • Addition and removal of acetyl groups from DNA
    http://www.universe-review.ca/F11-monocell.htm Epigenetic Mechanisms
  • Some Background Information
    • Deoxyribonucleic acid
    • Watson and Crick in 1953
    • Hold genetic instructions on we look and behave
    • Four nucleotides bases
      • Guanine
      • Adenine
      • Cytosine
      • Thymine
    http://instruct.westvalley.edu/svensson/CellsandGenes/ DNA-structure
  • Some Background Information (cont.)
    • DNA organized into chromosome
      • chromatin
    • Genes located on chromosome
    http://images1.clinicaltools.com/images/gene Chromosome Structure
  • Background Information
    • Central Dogma
      • DNA RNA protein
    • Transcription
      • DNA to RNA
    • Translation
      • RNA to protein
    Translation/transcription process
  • DNA Methylation
    • Addition of methyl groups to CpG sites
      • remains unmethylated at CpG islands
    • Most common method in gene silencing
    • Methylated gene
      • Inactive
      • Prevents transcription factors from binding to promoter
    • Non methylated gene
      • active
      • Transcription factors able to bind to promoter
  • Chromatin/Histone modifications
    • Addition and removal of acetyl groups from histones.
    • Addition of acetyl groups (acetylation) decondense chromatin, uncoiling the DNA strand which causes :
      • gene to become accessible to transcription factors, exposes promoter of gene.
      • transcribed gene-expression of gene
    • Removal of acetyl groups (deacetylation) cause chromatin to condense, tight coiling of DNA.
      • gene becomes inaccessible for transcription factors.
      • silent gene
  • Epigenetic Mechanisms for Repressing Transcription
    • Environ Health Perspect. 2006 March; 114(3): A160–A167
  • Role in Environment
    • Driven by multiple factors in environment:
      • Single nutrients
        • ex: maternal diet in rats, exposure to parents, grandparents during famine
      • Toxins- pesticides, smoking, drinking
        • ex: cancer
      • Behavior
        • ex: grooming of rat pups
  • Single nutrients
    • Study by Dr. Jirtle (2006) concerning epigenetic changes by dietary supplements
    • Epigenetic regulation of agouti gene
    • pregnant mothers diet
      • Vitamin B12, folic acid, choline and betaine.
      • brown coat color in offspring
      • inherited by next generation
    • pregnant mother diet
      • BPA
      • yellow coat color in offspring
    A pup of a different color . Supplementation of maternal diet with genistein and other compounds induced alterations in DNA methylation that were reflected in offspring coat color changes. Environ Health Perspect. 2006 March; 114(3): A160–A167 .
  • Famine
    • First proof of environmental effect being inherited in humans
    • Research by Marcus Pembrey and Olov Bygren(2008) concerning famine exposure
    • Effect of famine was different in grandmother and grandfather
      • Grandmother susceptible while still in the womb
      • Grandfather affected in late childhood
  • Famine
    • Women who experienced famine earlier in pregnancy had paternal granddaughters die earlier in life
      • Famine affected genetic makeup within X chromosome
      • IGF2 gene different in siblings not exposed
    • Men who experienced famine at age 10 had paternal grandsons that lived longer than those whose grandfathers didn’t experience famine
      • diabetes
    • You are what your parents and grandparents ate
  • Cancer
    • P-53: tumor suppressor gene
      • Excessive deacetylation/methylation silences gene
      • Results in uncontrollable cell growth
    • Epigenetic Therapy
      • Reactivating gene by removing methyl tags
  • Behavior
    • Study by Dr. Moshe Szyf (2004) showed that grooming, nursing, and licking of a rat pup can affect long-term behavior of offspring (p. 164).
      • Rats pups receiving high nurturing
        • methyl groups removed by nurturing signals, activated GR receptor gene-calm adults
      • Rats pups receiving low nurturing
        • methyl groups remain attached to DNA, inactivated (gene silenced) GR receptor gene-anxious adults
    • Hippocampus in pups
      • Production of GR protein (glucocorticoid receptor)
      • Cortisol (stress hormone) binds to these receptors
    • Affects more than just GR gene
  • Behavior
    • Epigenetic difference in high and low nurtured rats.
    • Can be reversed
      • Place pups with licking mother
      • Drugs that add and remove methyl tags
  • Twin Studies
    • Provide evidence of epigenetic influences in humans
    • Good way in determining heritability of disorders
      • MZ - same DNA, same sex
      • DZ - different DNA, different sex
    • Muhle et al. (2004) concordance rate
      • High concordance in MZ-60-90%
      • Low concordance in DZ- 0-10%
    • Fraga et al. (2005) showed epigenetic differences arise in older twins
      • Ex: cancer
  • Connection between Epigenetics and Autism
    • ASD comprises of a complex group of behaviorally related disorders that are genetic in origin
    • No single gene found
      • Multiple genes contribute to autism
        • Risch et al. (1999) found 2-15 genes contributing to susceptibility
      • Cannot be traced to single mutation or gene
    • Involvement of epigenetic regulatory mechanisms
  • Connection between Epigenetics and Autism (cont.)
    • Can use other disorders that share same clinical features to map out genetic and epigenetic components
    • Overlapping phenotypes
      • Rett Syndrome
      • Angelman’s syndrome and Prader-Willi syndrome
      • Fragile X syndrome
  • Chromosomes/Genes
    • 46 chromosomes (23 pairs)
    • 45-46: sex chromosomes
    • XX-woman
    • XY-man
    • Phenotype
      • Observable manifestation of trait
    • Genotype
      • Genetic constitution
  • Rett Syndrome
    • Neurological disorder classified as a PDD by the DSM-IV
    • Symptoms
      • cognitive impairments
      • problems with socialization
      • no verbal skills
    • X-linked neurodevelopmental disorder
    • Caused by mutations in the MECP2 gene on Xq25
    • n-Rett Syndrome
    • Mother Father
    • XX XⁿY
    • Children
    • XXⁿ XY
  • Fragile X syndrome
    • Genetic disorder caused by mutation of the FMR1 gene on the X chromosome
    • Some symptoms meet the diagnostic criteria for autism
    • X-linked dominant condition -girls: mild MR
        • -boys: severe MR
    • Mother Father
    • X X ª XY
    • X X ª X ª Y
  • Angelman Syndrome/Prader-Willi Syndrome
    • Both produced by same genetic mutation
      • AS: deletion of maternal copy, maternal mutation of UBE3A gene or UPD of chromosome 15q11-q13
      • Severe mental retardation, happy demeanor, non-verbal
      • PWS: deletion of paternal copy or UPD of chromosome 15q11-q13
      • Language, motor and developmental delays, excessive weight gain
    • Result from imprinting
    http://www.ucl.ac.uk/~ucbhjow/bmsi/bmsi_4.html AS/PWS Diagram
  • Methyl-CpG binding domain (MBD).
    • MBD1-gene
      • Mbd1: protein
    • MECP2-gene
      • MeCP2: protein
        • Multiple rules in regulating gene expression in neurons
    • Capable of binding specifically to methylated DNA
  • Fig. 1. The overlapping disorders, phenotypes and genotypes regulated by MECP2/MeCP2 through epigenetic mechanisms. AS, Angelman's syndrome; RTT, Rett syndrome.
  • Study
    • Study by Allan et al. (2008)
    • Mice lacking key regulatory protein Mbd1 show autism-like symptoms
    • Exhibit core deficits
      • reduced social interaction
      • learning deficits
      • anxiety
      • defective sensory motor gating
      • depression
      • abnormal serotonin activity
  • Study (cont.)
    • Methyl-CpG binding proteins (MBDs) are central components of DNA methylation-mediated epigenetic gene regulation.
    • Role in transcriptional repression
    • Mutation found in MBD1 gene in autistic patient and direct relatives
    • Analyzing Mbd1-/-
      • Understand role of Mbd1 in adult neurogenesis and learning
      • Understand importance of epigenetic regulation in mammalian brain development and cognitive functions.
  • Subjects
    • Mbd1-/- knockout (KO) mice
      • Mutant
      • No gross abnormality/ mild reduction of forebrain weight
      • Nearly normal lifespan
    • Mbd1 (WT)
      • Most common phenotype population
    • Sex
      • male and female
    • Age
      • 2-3 months
  • Methods
    • Social interaction
      • Place novel toy in tent for first 5min then mouse in for last 5min
    • Sensorimotor gating
      • PPI(Prepulse inhibition)
      • prepulse stimulus (auditory tone)
      • startle stimulus (air puff)
        • 120 and 300ms interstimulus interval
          • access how well they are able to inhibit stimulus
    • Learning deficits
      • Cued for fear conditioning and contextual fear conditioning
        • foot shocks to train mice
        • tested 24hrs later using auditory tone (cued test) and spatial context (context test)
          • learning and memory accessed by how long they freeze
    • t
  • Methods (cont.)
    • Anxiety
      • Light-dark preference test
      • Elevated plus-maze
        • Open arms
    • Susceptibility to depression
      • Learned helplessness test
        • foot shocks
      • Forced swim test
    • Serotonin receptor
      • Wet dog shake observed in behavioral experiments
        • indicator of increased serotonin activity
  • Results
    • Social Interaction
      • Mbd1-/-
        • Have normal motor activity and exploratory behavior
        • Reduced interest in social interaction
        • No gender differences
    Figure 1: Mbd1-/- mice have impaired social interaction Allan, A. M. et al. Hum. Mol. Genet. 2008 17:2047-2057; doi:10.1093/hmg/ddn102 Copyright restrictions may apply.
  • Results (cont.)
    • Sensorimotor Gating
      • Mbd1-/-
        • Impaired sensorimotor gating
    Allan, A. M. et al. Hum. Mol. Genet. 2008 17:2047-2057; doi:10.1093/hmg/ddn102 Figure 2: Mbd1-/- mice have impaired sensorimotor gating as assessed by prepulse inhibition (PPI) Copyright restrictions may apply.
  • Results (cont.)
    • Learning Deficits
      • Mbd1-/-
        • Exhibited deficits in fear-conditioning test-assessed amygdala-mediated learning.
        • Deficits in contextual fear conditioning test-assessed both hippocampus and amygdala mediated learning.
    Figure 3: Mbd1-/-mice exhibited deficits in fear-conditioning learning tests Allan, A. M. et al. Hum. Mol. Genet. 2008 17:2047-2057; doi:10.1093/hmg/ddn102 Copyright restrictions may apply.
  • Results (cont.)
    • Anxiety
      • Mbd1-/-
        • Increased anxiety
        • Spent less time in well-lit room
        • Spent less time in open arms and more in open arms
      • General locomotion same between genotypes (data not shown)
    Allan, A. M. et al. Hum. Mol. Genet. 2008 17:2047-2057; doi:10.1093/hmg/ddn102 Copyright restrictions may apply. Figure 4: Mbd1-/- mice exhibited increased anxiety
  • Results (cont.)
    • Susceptibility to depression
      • Mbd1-/-
        • Enhanced susceptibility to depressive behaviors
        • Longer latency in escaping shocks
        • Greater number of failed escapes
        • Exhibited more non-escape-directed behaviors and fewer escape-directed behaviors
    Figure 5: Mbd1-/- mice exhibited enhanced susceptibility to depressive behaviors Allan, A. M. et al. Hum. Mol. Genet. 2008 17:2047-2057; doi:10.1093/hmg/ddn102 Copyright restrictions may apply.
  • Other Findings
    • Loss of Mbd1 leads to elevated expression of Htr2c receptor.
      • Increased binding of serotonin to receptor
      • Receptors in hippocampus and medial frontal cortex
    • Htr2c does not function properly in Mbd1-/-
      • Low affinity of serotonin to receptor
    • Dysregulation of Htr2c
      • Abnormal serotonin system linked to autism
  • Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors: serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord. 1998;51:215-235
  • Copyright restrictions may apply. Allan, A. M. et al. Hum. Mol. Genet. 2008 17:2047-2057; doi:10.1093/hmg/ddn102 Mbd1 directly regulates the expression of serotonin receptor Htr2c
  • Current Research
    • Dr. Walter Kaufmann at Kennedy Krieger Institute and Dr. Andy Feinberg at Johns Hopkins University
      • compared brain scans of identical twins discordant for autism
      • found that hippocampus smaller in twin with severe autism
      • Hypothesis: since genome the same, one has epigenetic change
      • Searching for methyl marks in DNA
  • Future Studies
    • Recent attention of epigenetics in ASD
    • Autism Speaks: $3.6 million to investigate environmental risk factors for autism
    • Dr. Yong-hui Jiang at Baylor College of Medicine
      • how folic acid supplementation affects epigenetic modulation of SHANK3 protein expression
    • Dr. Robert Plomin at Institute of Psychiatry in London
      • Looking at epigenetic markers in twins who do not share dianosis of autism.
  • Future Studies (cont.)
    • Dr. Emile Rissman at University of Virginia
      • BPA (Bisphenol A)
    • Dr. Bruce Hammock at University of California at Davis
      • Vitamin D levels
        • lack of Vitamin D could influence brain development and function
    • It’s too early to speculate on treatment for epigenetic factors, but mouse models should help evaluate treatment
  • References
    • Allan, A.M., Liang, W., Luo,Y., Pak, C., Li, X., Szulwach, K.E., Chen, D., Jin, P., Zhao, (2008). The loss of methyl-CpG binding protein 1 leads to autism-like behavioral deficits. Human Molecular Genetics, 17(13) , 2047-2057.
    • Fraga, M.F., Ballestar, E., Paz, M.F., Ropero, S., Setien, F., Ballestar, M.L.., et al. (2005). Epigenetic differences arise during the lifetime of monozygotic twins. PNAS, 102(30) , 10604- 10609.
    • Jirtle, R.L., Dolinoy, D.C., Weidman, J.R., Waterland, R.A. (2006). Maternal genistein alters coat color and protects mouse offspring from obesity by modifying fetal epigenome. Environmental Health Perspectives, 114(4), 567-572.
    • Lewis, M., Lopez-Rangel, E. (2006). HotSpots: Loud and clear evidence for gene silencing by epigenetic mechanisms in autism spectrum and related neurodevelopmental disorders. Clinical Genetics, 69 , 21-25.
    • Muhle, R., Trentacoste, S.V., Rapin, I. (2004). The genetics of autism, Pediatrics, 113(5), 472-486.
    • Pembrey, M.E, Bygren, L.O., Kaati, G. (2008). Sex-specific male-line transgenerational responses in humans. Human Genetics, 14, 159-166.
    • Risch, N., Spiker, D., Lotspeich, L., Nouri, N., Hinds, D., Hallmayer, J., et al. (1999). A geomic screen of autism: evidence for a multilocus etiology. Human Genetics, 65, 493-507.
    • Szyf, M., Weaver, I.C.G., Cervoni, N., Champagne, F.A., D’Alessio, A.C., Sharma, S., et al. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7(8), 847-854.
    • Weinhold, B. (2006). Epigenetics: The science of change. Environmental Health Perspective, 114(3), 160-167.