Autism’s hyperlink to chromatin transforming, defined | Spectrum
Autism research has long focused on genes involved in the formation of neurons and the function of synapses. Mutations in these genes were the first to be firmly linked to the disease and its characteristics. Over the past decade, however, several studies have implicated a second class of genes: those involved in remodeling chromatin – the complex of DNA and proteins that make up chromosomes.
These “chromatin regulators,” which can affect whether other genes are turned on or off, are sometimes mutated in people with autism or other neurodevelopmental disorders. Scientists are only just beginning to understand how these mutations can alter brain development.
Why is chromatin remodeling important?
If the chromosomes of a single human cell were stretched out and joined end to end, its DNA would be about 6.5 feet long. To fit inside a nucleus no wider than a tenth of a human hair, the strand of DNA wraps around histone proteins to form a series of bead-like structures called nucleosomes. Together these pearls form the chromatin.
When a stretch of DNA is tightly packed in a nucleosome, it is inaccessible to the proteins that turn genes on and off through a process called transcription. In order for cells to express the right genes at the right time, their DNA must transition from tightly packed to loosely packed coils, a process carried out by a group of proteins called chromatin remodeling complexes.
Mutations in certain components of these complexes have been linked not only to autism but also to cancer, schizophrenia, intellectual disability, and other diseases. The structure of chromatin is also regulated by enzymes that add or remove specific chemical labels on DNA and histone proteins. Mutations have been found in some of these enzymes in people with autism or intellectual disabilities.
How do we know chromatin remodeling is linked to autism?
Genes involved in chromatin regulation are significantly more likely to be disrupted in autistic children than in their unaffected siblings, according to four large sequencing studies published in 2012. Mutations in one such gene, called CHD8, can account for up to 0.4 percent of autism cases. another study showed.
In fact, the list of genes most surely linked to autism that has been gleaned from recent large-scale sequencing efforts includes CHD8 and other chromatin regulators such as ARID1B, ASH1L, KMT2A, and SETD5. Even mutations in non-coding parts of the genome of people with autism appear to affect chromatin structure.
Some chromatin regulators associated with autism, including ACTL6B, are part of a chromatin remodeling complex known as BAF. Mutations in ACTL6B are recessive, which means that they are only harmful if a person inherits two copies. Most of the other chromatin remodeling mutations associated with autism are not inherited, but arise spontaneously in the egg, sperm, or fertilized egg.
How do mutations in chromatin remodeling factors lead to autism?
It’s unclear. Scientists suspect that chromatin regulators are important for brain development. By regulating gene expression, chromatin remodeling can influence the formation and differentiation of neurons. In line with this idea, a large 2019 study revealed a network of autism-related genes involved in chromatin remodeling during new neuron growth.
The protein encoded by CHD8, one of the most commonly mutated genes in people with autism, inhibits the function of an important signaling protein called beta-catenin. And mutations in a group of genes that CHD8 belongs to appear to increase connectivity between areas of the brain involved in sensory processing. Autistic people with CHD8 mutations often have intellectual disabilities and a larger than average head. Mutations in CHD8 can affect brain growth by controlling the proliferation of cells that make neurons in the cortex – the outer layer of the brain.
The BAF complex also has some fascinating connections to brain development. Parts of a neuron-specific chromatin regulator called nBAF are mutated in autism, and researchers have shown that the loss of a BAF component expressed in neuronal precursors can disrupt the formation of new neurons in mice. Rodents lacking a BAF component expressed in mature neurons tend to have normal neuronal development, but their brain cells do not grow in response to activity, as typical neurons do. This leads to behavior similar to autism and deficits in spatial memory and object recognition.
What about mutations in enzymes that modify histones?
Chemical modifications can alter the structure of histone proteins and change the way genes are exposed and transacted to be read. The genomic patterns of such a modification, known as acetyl-tag, differ between the brains of some autistic people and those of control subjects.
In fact, mutations in enzymes that add and remove chemical tags from histones have been linked to autism and other neurodevelopmental disorders. For example, SETD5, a leading autism gene, encodes an enzyme that is believed to add a methyl group to a particular histone, altering the expression of hundreds of other genes. Researchers have found that mouse neurons lacking a copy of SETD5 make fewer connections than control neurons.
Do environmental factors interact with genetic risk factors in changing the chromatin structure?
Scientists know that consuming alcohol or taking medications such as the epilepsy drug valproate during pregnancy can alter the chromatin structure of the fetus. Female mice exposed to flame retardant polybrominated diphenyl ether (PDBE) before birth had reduced DNA methylation – a chemical alteration in DNA that alters gene expression – and problems with learning and memory. Some of these problems appear to worsen after exposure to PDBE in a mouse model of Rett syndrome, a rare condition often accompanied by autism. These mice have a mutation in MECP2, a protein that binds to methylated regions of DNA and regulates the expression of other genes. So one possibility is that genes and the environment can be combined to alter chromatin structure, resulting in changes in gene expression and behavior.
Could Chromatin Remodeling Drugs Help Relieve Some Autism Features?
May be. Compounds that affect chromatin remodeling are used as cancer therapies, and some have shown promise in autism as well. For example, an anti-cancer drug that blocks a family of enzymes called HDACs that remove acetyl tags from histones can alleviate some autism-like features in mice lacking part of SHANK3 – a gene found in up to 2 percent of people with autism is mutated.
Mice lacking SHANK3 have too much of a specific HDAC protein and fewer acetyl groups in their brain than controls. The mice also show increased expression of two histone-modifying enzymes, EHMT1 and EHMT2, which have been implicated in autism and autism-like conditions. Giving the mice a compound that inhibits EHMT enzymes increased the animals’ social interest, but had no effect on motor function, anxiety, or repetitive behavior.
Because chromatin remodeling occurs in all cell types, compounds that block it often have undesirable side effects. In search of safer alternatives, researchers are exploring other strategies to target chromatin. One promising approach is using the gene editing technology CRISPR to modify the chemical markings of the genome that control chromatin structure and gene expression. This approach could help control the activity of genes associated with autism and alleviate some of the characteristics of the condition.
