Epigenetic Etiology of Intellectual Disability

Abstract

Intellectual disability (ID) is a prevailing neurodevelopmental condition associated with impaired cognitive and adaptive behaviors. Many chromatin-modifying enzymes and other epigenetic regulators have been genetically associated with ID disorders (IDDs). Here we review how alterations in the function of histone modifiers, chromatin remodelers, and methyl-DNA binding proteins contribute to neurodevelopmental defects and altered brain plasticity. We also discuss how progress in human genetics has led to the generation of mouse models that unveil the molecular etiology of ID, and outline the direction in which this field is moving to identify therapeutic strategies for IDDs. Importantly, because the chromatin regulators linked to IDDs often target common downstream genes and cellular processes, the impact of research in individual syndromes goes well beyond each syndrome and can also contribute to the understanding and therapy of other IDDs. Furthermore, the investigation of these disorders helps us to understand the role of chromatin regulators in brain development, plasticity, and gene expression, thereby answering fundamental questions in neurobiology.

Keywords: Claes-Jensen syndrome; DNA methylation; Kleefstra syndrome; Rett syndrome; Rubinstein-Taybi syndrome; X-linked intellectual disability; histone posttranslational modification; neuroepigenetics; α-thalassemia mental retardation syndrome.

Figure 1.

Six important chromatin-related IDDs. The six IDDs discussed in this review are caused by mutations in different chromatin regulators that converge in related molecular processes. In the scheme, these chromatin factors are depicted in the proximity of their respective chromatin targets. All the acetylation marks presented in the scheme are possible substrates of KAT3 proteins. K, lysine; 5meC, 5-methylcytosine.

Figure 2.

From identification of ID-related genes to therapy. Schematic representation of the long, and still unaccomplished, path that goes from the identification of the IDD-causing mutation to therapy. After identification of the mutation, the generation and characterization of animal model reproducing the same genetic defects enable the description of the molecular mechanisms underlying the disease and the assessment of therapies. Complementing the studies of animal models, iPSCs derived from the patients can be also used to investigate pathoetiology and assess possible therapies. Therapeutic strategies that provide positive results in the cellular and animal models, such as drug treatment and gene editing or epi-editing, will be eventually evaluated in clinical trials.