Chromatin

Defining chromatin:

Chromatin is the name given to the coiled complex of DNA and protein found in the nucleus of the cell that helps to regulate gene expression. The tight association of DNA with proteins called histones is necessary for the compaction and organization of DNA in the nucleus. Factors that alter the structure of chromatin can modulate access of transcription factors to a DNA sequence. For example, heavily compacted regions of chromatin may be inaccessible to these factors and genes within these regions are switched off in that particular cell. [1].

Many enzymes have evolved that can modify chromatin and thereby change its structure. These enzymes, which usually function in large complexes with multiple subunits, have important roles in regulating gene expression. For instance, Polycomb repressive complexes repress gene expression by compacting chromatin structure, whilst Trithorax proteins promote the opening of chromatin structure. [2]

Relevance to autism:

It has been known for many years that the mutation of genes encoding chromatin modifying or remodelling factors can cause human syndromes.

It has been known for many years that the mutation of genes encoding chromatin modifying or remodelling factors can cause human syndromes. For example, Wiedemann-Steiner syndrome, a rare condition associated with distinctive facial features, short stature, hairy elbows and intellectual disability is caused by dominant mutations in the KMT2A gene, which encodes an enzyme that introduces a specific histone modification called H3K4me3. [3] CHARGE syndrome is caused by mutations in a gene called CHD7, which can remodel chromatin to make it more accessible. [4]

Recent large-scale gene sequencing studies in autism cohorts like the Simon’s Simplex Collection have identified mutations in several genes encoding chromatin modifying or remodelling factors in individuals with autism [5,6, 7, 8, 9]. The majority of these mutations were de novo, i.e. not inherited from the parents and typically not found in the control population. Thus, these genes, which include CHD8, ARID1B, ASH1L, KMT2A and SETD5, are some of the highest confidence autism genes identified to date. Some of these gene mutations are causes of known syndromes associated with autism and intellectual disability, for example, Wiedemann Steiner syndrome and Coffin-Siris syndrome. Interestingly, people with mutations in these genes often display a complex constellation of phenotypes suggesting that these gene mutations cause hitherto unrecognized syndromes associated with autism and intellectual disability. People with CHD8 mutations have characteristic facial features, macrocephaly and tall stature, in addition to autism.

The SFARI gene list, which currently lists >800 genes implicated in autism, includes over 50 factors that may control chromatin structure. Over one third of high confidence autism risk genes encode factors that can regulate chromatin structure, with a further 8 such genes within the 53 so-called ‘strong candidate genes’ identified to date.

Current questions:

These findings raise several important questions. The first question is obvious: How does the mutation of these factors alter brain development to result in autism and intellectual disability? This is not a trivial question as most of these factors potentially regulate the expression of hundreds of other genes, at multiple key stages of brain development and in several different brain regions. The CHD8 gene illustrates this point nicely. In early neural progenitor cells, CHD8 appears to fine-tune the expression of many other autism-associated genes. Studies of CHD8-deficient mouse models support this idea, and further show that the changes in gene expression during brain development are relatively mild, leading to the notion that the neurodevelopmental phenotype associated with CHD8 deficiency is the result of dysregulated expression of multiple genes [10, 11, 12]. The next question is one of convergence. Do mutations of these chromatin factors eventually all affect the same or similar neurodevelopmental processes? One possibility might be that many of these factors control the expression of genes involved in regulating connectivity in the brain, i.e. genes that encode axon guidance or synaptic proteins. The identification of convergence would be important, if only by helping to simplify the ever-increasing complexity of autism’s aetiology.

In conclusion, recent human genetic findings provide strong evidence to suggest that alterations in chromatin structure may underlie a significant proportion of autism cases and other related neurodevelopmental disorders. Perhaps unexpectedly, these findings also indirectly point towards a possible point of convergence of genetic and non-genetic, or environmental causes of autism. Factors that include early life stress and lack of maternal care, or exposure to the anti-convulsant, valproic acid, during pregnancy are known to alter chromatin structure. [13] It may therefore not be too far-fetched to propose that these non-genetic factors interact with genetic risk factors by altering chromatin structure. Indeed, human epigenomic studies have reported differences in the distribution of specific chromatin modifications in the brains of individuals with autism.[14] Whether these changes are caused by specific genetic or environmental risk factors, or merely incidental, will need to be confirmed. Direct comparisons of chromatin alterations in genetically-defined autism cases or even mouse models will be highly informative.

Finally, the realization that changes in chromatin structure may cause autism and neurodevelopmental disorders, also creates an opportunity to discover novel treatment options. Chromatin structure is not fixed, and a whole range of pharmacological compounds that can alter the chromatin landscape have been identified and are showing promise as cancer therapies. With the caveat that most of these are likely to have unwanted side-effects, the possibility that drugs, or other approaches that target chromatin may in the future become available to treat some of the most debilitating autism features seems closer than before.