User:Kelsidc/Main Sandbox

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

Lead:

• good Definition of autism and autism spectrum disorder
• good definition of epigenetics
• What are the general ways that epigenetics has been applied to autism?

Epigenetic Causes of ASD [or "Autism"?]

15q11-13 duplication

In humans, chromosome 15q11-13 is the location of a number of mutations that have been associated with Autism spectrum disorders (ASD).

Duplications of 15q11-13 are associated with about 5% of patients with ASD and about 1% of patients diagnosed with classical Autism. 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 phenotypes associated with 15q11-13 duplications. "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.) Genes that are deficient in paternal or maternal 15q11-13 alleles result in Prader-Willi or Angelman syndromes, respectively, and duplications in the maternal copy lead to a distinct condition that often includes autism. 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. 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:

• GABA_A 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 and multiple genetic studies have found significant evidence for association. Furthermore, a significant decrease in abundance of GABRB3 has been reported in the brain of AS, AUT and RTT patients. Other GABA receptors residing on different chromosomes have also been associated with autism (e.g. GABRA4 and GABRB1 on chromosome 4p).

• 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. Patients with autism have also shown abnormalities in methylation of the UBE3A CpG island.

• 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).

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.

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.

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) However, chromatin immunoprecipitation and bisulfite sequencing have demonstrated that MeCP2 binds to methylated CpG sites within GABRB3 and the promoter of SNRPN/SNURF.

Furthermore, homologous 15q11-13 pairing in neurons that is disrupted in RTT and autism patients, has been shown to depend on MeCP2. 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. Talk to me Monday at office hours if you don't understand how to do this.

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.
• 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).