Main mechanisms of epigenetic alterations in autism. Each alteration involves many enzymes but the main players to cause methylation or acetylation are shown by arrows. These are not separate mechanisms and the enzymes do not act alone. Several enzymes act at a promoter simultaneously. (1) Low methyl CpG binding protein-2 (MeCP2) at CpG islands of frontal cortex reduces capacity for complexing with histone deacetylase 1 (HDAC1) for gene silencing. (2) HDAC1 inhibition by valproic acid exposure and glycogen synthetase kinase-3B (GSK3B) inhibition by lithium upregulate Wnt signaling pathway and activate transcription, associated with macrocephaly with increased number of cerebral cortical column. (3) DNA methyltransferase (DNMT) methylates oxytocin receptor gene produces low oxytocin and estrogen activity necessary for androgen receptor mediated high-arousal inputs to amygdala. (4) Histone H3 phosphorylation by protein kinase C beta activates the histone methyltransferase (HMT) lysine demethylase 1 (LSD1) which prevents demethylation of lysine-4 site of histone-3 (H3K4) that is also necessary for androgen receptor (AR) mediation of high arousal inputs to amygdala. (5) Maternal hypomethylation by dietary folic acid deficiency decreases availability of S-adenosyl methionine (SAM), associated with abnormal intrauterine growth.
