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Epigenetics of Autism--Outline. People playing in this sandbox are: Kelsi Cox, Valentina, Ria, Christina

Lead:

Autism Spectrum Disorder refers to a variety of conditions typically identified by challenges with social skills, communication, speech, and repetitive sensory-motor behaviors. This disorder tends to be have a strong correlation with genetics along with other factors. More research is identifying ways in which epigenetics is linked to autism. Epigenetics generally refers to the ways in which chromatin structure is altered to effect gene expression.

Epigenetic Causes of ASD

Increased Cortical Excitability

One of the leading theories of the cause of ASD, in epigenetics and in biology more broadly, is cortical hyperexcitability. There are many genetic and epigenetic factors that can contribute to increased excitability, but one of the mechanisms implicated in ASD is modification of chromosome 15q11 to q13 modification. These regions of chromosome 15 contain genes encoding subunits of GABA receptors.[1] GABA is the main neurotransmitter implicated in inhibition in the cortex of mammalian brains;[2] changes to this cortical inhibitory system can result in increased excitability, through either deletion or duplication of the 15q11-13 region.[1]

15q11-13 duplication

Duplications of 15q11-13 are associated with about 5% of patients with ASD[3] and about 1% of patients diagnosed with classical Autism.[4] 15q11-13 in humans contains a cluster of genetically imprinted genes important for normal neurodevelopment. (Table 1) Like other genetically imprinted genes, the parent of origin determines the phenotypesassociated with 15q11-13 duplications.[5] "Parent of origin effects" cause gene expression to occur only from one of the two copies of alleles that individuals receive from their parents. (For example, MKRN3 shows a parent of origin effect and is paternally imprinted. This means that only the MKRN3 allele received from the paternal side will be expressed.) Duplications in the maternal copy lead to a distinct condition that often includes autism.[6]

15q11-13 deletion

Genes that are deficient in paternal or maternal 15q11-13 alleles result in Prader-Willi or Angelman syndromes, respectively. Overexpression of maternally imprinted genes is predicted to cause autism, which focuses attention to the maternally expressed genes on 15q11-13, although it is still possible that alterations in the expression of both imprinted and bilallelically expressed genes contribute to these disorders.[6] The commonly duplicated region of chromosome 15 also includes paternally imprinted genes that can be considered candidates for ASD.

Genes on 15q11-13 can be classified into three main categories:

  • GABAA receptor genes:

Members of the GABA receptor family, especially GABRB3, are attractive candidate genes for Autism because of their function in the nervous system. Gabrb3 null mice exhibit behaviors consistent with autism[7] and multiple genetic studies have found significant evidence for association.[8] Furthermore, a significant decrease in abundance of GABRB3 has been reported in the brain of AS, AUT and RTT patients.[9] Other GABA receptors residing on different chromosomes have also been associated with autism (e.g. GABRA4 and GABRB1 on chromosome 4p).[10]

  • Maternally imprinted genes:

There are two maternally imprinted genes in 15q11-13, UBE3A and ATP10A (Table 1) and both lie toward the centromeric end. Both these genes are important candidates for ASD. Significant decrease in UBE3A abundance has been observed in post mortem brain samples from patients with AUT, AS and RT.[11] Patients with autism have also shown abnormalities in methylation of the UBE3A CpG island.[12]

  • Paternally imprinted genes:

Most of the genes in 15q11-13 are paternally expressed. Gene expression analysis of paternally expressed imprinted genes has revealed that, in some cases excess of maternal 15q11-13 dosage can cause abnormal gene expression of the paternally expressed genes as well (even though the paternal 15q11-13 is normal).[13]

Regulation of gene expression in 15q11-13:

Regulation of gene expression in the 15q11-13 is rather complex and involves a variety of mechanisms such as DNA methylation, non-coding and anti-sense RNA.[14]

The imprinted genes of 15q11-13 are under the control of a common regulatory sequence, the imprinting control region (ICR). The ICR is a differentially methylated CpG island at the 5′ end of SNRPN. It is heavily methylated on the silent maternal allele and unmethylated on the active paternal allele.[15]

MeCP2, which is a candidate gene for Rett syndrome, has been shown to affect regulation of expression in 15q11-13. Altered (decreased) expression of UBE3A and GABRB3 is observed in MeCP2 deficient mice and ASD patients. This effect seems to happen without MeCP2 directly binding to the promoters of UBE3A and GABRB3. (Mechanism unknown)[16] However, chromatin immunoprecipitation and bisulfite sequencing have demonstrated that MeCP2 binds to methylated CpG sites within GABRB3 and the promoter of SNRPN/SNURF.[17]

Furthermore, homologous 15q11-13 pairing in neurons that is disrupted in RTT and autism patients, has been shown to depend on MeCP2.[18] Combined, these data suggest a role for MeCP2 in the regulation of imprinted and biallelic genes in 15q11-13. However, evidently it does not play a role in the maintenance of imprinting.[17]

Histone deacetylases (HDACs) and ASD

  • The strongest link of HDACs to ASD has been found in prenatal HDAC inhibition research. Valproic acid (VPA) is a weak HDAC inhibitor that has been shown to increase the risk of ASD in pregnant moms that use it. Valproic acid is an anticonvulsant (used to treat seizures/ epilepsy). In mice studies, prenatal exposure to trichostatin A (TSA) and VPA (both are HDAC inhibitors) lead to ASD symptoms. To add, mRNA levels of Nlgn1, Shank2, Shank3, and Cntnap2 (genes related to synaptogenesis) were changed from TSA inhibition. These genes are linked to ASD as well.(Tseng et al., 2021)
  • Studies have found that the prenatal exposure of VPA in mice causes hyperacetylation (increased acetylation) of histones H3 and H4 which is associated with the ASD related symptoms postnatally. However, prenatal exposure to valpromide, which is similar to VPA but not an HDAC inhibitor, does not cause hyperacetylation of histones H3 and H4 and ASD related symptoms. These findings suggest that HDAC has a role in ASD during a certain part of brain development ----- REWORD(Nicolin et al, 2018)
  • Clinical studies have found an association between in utero exposure to VPA and ASD. There is a high prevalence rate of ASD symptoms among children with fetal valproate syndrome (FVS). FVS is a rare condition in children that happens due to VPA exposure during the first trimester of pregnancy.
  • HDAC inhibitors (VPA and TSA) in prenatal mice models increase histone acetylation and decrease HDAC expression. Decreases social interactions / behavior observed in mice, rats, voles and non human primates exposed to VPA prenatally on E12.5 (embryonic day). Decreases social behavior primarily observed in males and sometimes females displayed no social deficits. Exposures on different embryonic days had not results in social deficits/ decreased social behavior in adolescents rodents. Long term effects of HDAC inhibition may differ from immediate effects,
  • Post natal HDAC inhibition has the opposing effects. ASD symptoms can be improved. Romidepsin and MS-275 (HDAC inhibitors) improves social behaviors (preference and interaction time) in Shank3- deficient mice. TSA increases histone acetylation at the oxytocin and vasopressin receptors of the nucleus accumbens (NA) in female voles (like pair bonding). Beta hydroxybutyrate (a product of the ketogenic diet and inhibitor of class 1 HDAC) has shown to improve social behavior/skills in children (small clinical trials).

Potential Applications of Epigenetic Research to Treatment of ASD

New References (already added in text; rewritten here so we can keep track)

Neural Hyperexcitability in Autism Spectrum Disorders

GABA and glutamate in the human brain

Genetics and epigenetics of autism: A Review[19]

"Epigenetics of Autism Spectrum Disorder: Histone Deacetylases"[20]

Epigenetics and autism[21]

The valproic acid- induced rodent model of Autism[22]

References

Genetics and epigenetics of autism: A Review[19]

  1. ^ a b Takarae, Yukari; Sweeney, John (2017-10-13). "Neural Hyperexcitability in Autism Spectrum Disorders". Brain Sciences. 7 (10): 129. doi:10.3390/brainsci7100129. ISSN 2076-3425. PMC 5664056. PMID 29027913.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  2. ^ Petroff, Ognen A. C. (2002-12). "GABA and glutamate in the human brain". The Neuroscientist: A Review Journal Bringing Neurobiology, Neurology and Psychiatry. 8 (6): 562–573. doi:10.1177/1073858402238515. ISSN 1073-8584. PMID 12467378. {{cite journal}}: Check date values in: |date= (help)
  3. ^ Schanen N. C. (2006). "Epigenetics of autism spectrum disorders". Human Molecular Genetics. 15: R138 – R150. doi:10.1093/hmg/ddl213. PMID 16987877.
  4. ^ Samaco, R. C.; Hogart, A. & LaSalle, J. M. (2005). "Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3". Human Molecular Genetics. 14 (4): 483–492. doi:10.1093/hmg/ddi045. PMC 1224722. PMID 15615769.
  5. ^ Cook, E.H., Jr.; Lindgren, V.; Leventhal, B.L.; Courchesne, R.; Lincoln, A.; Shulman, C.; Lord, C. & Courchesne, E. (1997). "Autism or atypical autism in maternally but not paternally derived proximal 15q duplication". American Journal of Human Genetics. 60 (4): 928–934. PMC 1712464. PMID 9106540.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ a b Hogart, A. (2009). "Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alteration in gene expression not predicted from copy number". Journal of Medical Genetics. 46 (2): 86–93. doi:10.1136/jmg.2008.061580. PMC 2634820. PMID 18835857.
  7. ^ Klose, R.J. & Bird, A.P. (2006). "Genomic DNA methylation: the mark and its mediators". Trends in Biochemical Sciences. 31 (2): 89–97. doi:10.1016/j.tibs.2005.12.008. PMID 16403636.
  8. ^ Kriaucionis, S. & Bird, A. (2003). "DNA methylation and Rett syndrome". Human Molecular Genetics. 12 (2): R221 – R227. doi:10.1093/hmg/ddg286. PMID 12928486.
  9. ^ Pickles, A.; Bolton, P.; Macdonald, H.; Bailey, A.; Le Couteur, A.; Sim, C.H. & Rutter, M. (1995). "Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism". American Journal of Human Genetics. 57 (3): 717–726. PMC 1801262. PMID 7668301.
  10. ^ Ma, D.Q.; Whitehead, P.L.; Menold, M.M.; Martin, E.R.; Ashley-Koch, A.E.; Mei, H.; Ritchie, M.D.; Delong, G.R.; Abramson, R.K.; Wright, H.H.; et al. (2005). "Identification of significant association and gene – gene interaction of GABA receptor subunit genes in autism". American Journal of Human Genetics. 77 (3): 377–388. doi:10.1086/433195. PMC 1226204. PMID 16080114.
  11. ^ Samaco, R. C.; Hogart, A. & LaSalle, J. M. (2005). "Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3". Human Molecular Genetics. 14 (4): 483–492. doi:10.1093/hmg/ddi045. PMC 1224722. PMID 15615769.
  12. ^ Jiang YH; Sahoo T; Michaelis RC; Bercovich D; Bressler J; Kashork CD; Liu Q; Shaffer LG; Schroer RJ; Stockton DW; Spielman RS; Stevenson RE; Beaudet AL (2004). "A mixed epigenetic/genetic model for oligogenic inheritance of autism with a limited role for UBE3A". American Journal of Medical Genetics. 131 (1): 1–10. doi:10.1002/ajmg.a.30297. PMID 15389703. S2CID 9570482.
  13. ^ Hogart, A.; et al. (Feb 2009). "Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number". Journal of Medical Genetics. 46 (2): 86–93. doi:10.1136/jmg.2008.061580. PMC 2634820. PMID 18835857.
  14. ^ Nicholls, R.D. & Knepper, J.L. (2001). "Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes". Annu. Rev. Genom. Hum. Genet. 2: 153–175. doi:10.1146/annurev.genom.2.1.153. PMID 11701647.
  15. ^ Hogart, A.; et al. (Feb 2009). "Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number". Journal of Medical Genetics. 46 (2): 86–93. doi:10.1136/jmg.2008.061580. PMC 2634820. PMID 18835857.
  16. ^ Pickles, A.; Bolton, P.; Macdonald, H.; Bailey, A.; Le Couteur, A.; Sim, C.H. & Rutter, M. (1995). "Latent-class analysis of recurrence risks for complex phenotypes with selection and measurement error: a twin and family history study of autism". American Journal of Human Genetics. 57 (3): 717–726. PMC 1801262. PMID 7668301.
  17. ^ a b Samaco, R. C.; Hogart, A. & LaSalle, J. M. (2005). "Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3". Human Molecular Genetics. 14 (4): 483–492. doi:10.1093/hmg/ddi045. PMC 1224722. PMID 15615769.
  18. ^ Hogart, A.; et al. (2007). "15q11-13 gabaa receptor genes are normally biallelically expressed in brain yet are subject to epigenetic dysregulation in autism spectrum disorders". Human Molecular Genetics. 16 (6): 691–703. doi:10.1093/hmg/ddm014. PMC 1934608. PMID 17339270.
  19. ^ a b Waye, Mary M. Y.; Cheng, Ho Yu (2018-04). "Genetics and epigenetics of autism: A Review: Genetics and epigenetics of autism". Psychiatry and Clinical Neurosciences. 72 (4): 228–244. doi:10.1111/pcn.12606. {{cite journal}}: Check date values in: |date= (help)
  20. ^ Tseng, Chieh-En Jane; McDougle, Christopher J.; Hooker, Jacob M.; Zürcher, Nicole R. (2021-12). "Epigenetics of Autism Spectrum Disorder: Histone Deacetylases". Biological Psychiatry: S0006322321018321. doi:10.1016/j.biopsych.2021.11.021. {{cite journal}}: Check date values in: |date= (help)
  21. ^ Mbadiwe, Tafari; Millis, Richard M. (2013). "Epigenetics and Autism". Autism Research and Treatment. 2013: 1–9. doi:10.1155/2013/826156. ISSN 2090-1925. PMC 3787640. PMID 24151554.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  22. ^ Nicolini, Chiara; Fahnestock, Margaret (2018-01). "The valproic acid-induced rodent model of autism". Experimental Neurology. 299: 217–227. doi:10.1016/j.expneurol.2017.04.017. {{cite journal}}: Check date values in: |date= (help)
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