Autism genes keep turning up chromatin

Abstract

Autism-spectrum disorders (ASD) are complex genetic disorders collectively characterized by impaired social interactions and language as well as repetitive and restrictive behaviors. Of the hundreds of genes implicated in ASD, those encoding proteins acting at neuronal synapses have been most characterized by candidate gene studies. However, recent unbiased genome-wide analyses have turned up a multitude of novel candidate genes encoding nuclear factors implicated in chromatin remodeling, histone demethylation, histone variants, and the recognition of DNA methylation. Furthermore, the chromatin landscape of the human genome has been shown to influence the location of de novo mutations observed in ASD as well as the landscape of DNA methylation underlying neurodevelopmental and synaptic processes. Understanding the interactions of nuclear chromatin proteins and DNA with signal transduction pathways and environmental influences in the developing brain will be critical to understanding the relevance of these ASD candidate genes and continued uncovering of the "roots" of autism etiology.

Keywords: environment; epigenetics; epigenomics; genetics; genomics; metabolism; neurodevelopment; nutrition.

Figure 1. Chromatin factors at the roots of autism etiology

An analogy of a tree with deep roots is used to illustrate several points about chromatin factors implicated in autism. Candidate gene approaches for ASD have justifiably prioritized the investigation of low hanging fruit (large red circles) for genes that encode proteins with known functions at neuronal synapses. But these synaptic proteins are connected to signal transduction pathways that make changes to gene expression patterns through chromatin dynamics within the neuronal nucleus. The mTOR pathway, which integrates metabolic and nutrient sensing signals into energy is central to the signaling pathways and to supplying energy for chromatin remodeling events. But just as the roots and trunk of a tree are bidirectional pathways for the tree, information within the nucleus stored in the form of chromatin provides information back to the synapse to regulate levels of synaptic proteins during synaptic pruning and scaling. Levels of DNA methylation (small red dots) and readers of DNA methylation (MECP2, MBD1, etc) may act as chromatin sensors of many environmental factors including diet and chemical toxins during the maturation of synapses. Furthermore, chromatin factors such as MACROD2 and JMJD1C have metabolic sensing properties, so that factors such as stress and inflammation may alter chromatin dynamics of neurons with long lasting effects. Thus, in the future, it will be important to continue to dig beneath the surface to unearth the chromatin factors and epigenetic pathways in the etiology of ASD in order to fully understand these complex genetic disorders.