1. Epigenetics of Autism Spectrum Disorder Chinyelu Mozie University of Texas at Dallas March 25, 2009
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28. Fig. 1. The overlapping disorders, phenotypes and genotypes regulated by MECP2/MeCP2 through epigenetic mechanisms. AS, Angelman's syndrome; RTT, Rett syndrome.
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40. 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
41. 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
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Editor's Notes
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
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