New research from Japan’s RIKEN Center for Brain Science (CBS) shows that a histone methylation deficiency could lead to the development of Autism Spectrum Disorders (ASD). A human variant of the SUV39H2 gene led researchers to examine its absence in mice. Published in Molecular psychiatry, the study found that when adult mice were absent, they exhibited cognitive flexibility similar to that produced in autism, and embryonic mice showed poorly regulated expression of genes related to brain development. These findings represent the first direct link between SUV39H2 gen and TEA.
Genes are turned on and off throughout our development. But genetic variation it means that what is disabled in some people remains activated in others. This is why, for example, some adults can digest dairy products and others are lactose intolerant; the gene to produce the enzyme lactase is inactivated when some people become adults, but not others. One way that people it can be activated and deactivated by a process called histone methylation in which special enzymes transfer methyl groups to proteins in the histones that surround the DNA.
Variations in methylation-related genes during brain development can cause serious problems. One of these variations occurs in a rare disorder called Kleefstra syndrome, in which a mutation prevents the methylation of H3K9, a specific location in histone H3. Because Kleefstra syndrome is somewhat similar to autism, researchers at RIKEN CBS led by Takeo Yoshikawa looked for specific variations of autism in genes that could modify H3K9. Among nine such genes, they found a variant in a H3K9 methyltransferase gene, SUV39H2, that was present in autism, and the mutated SUV39H2 prevented methylation when tested in the laboratory. Similar loss of function results were found for the mouse version of the variant.
The next step was to see what happens in mice that do not have the Suv39h2 gene. Behaviorally, the researchers found that mice could learn a simple cognitive task, but that they had difficulty when the task required cognitive flexibility. In the simple task, the mice learned to get a reward by punching a door at the alternate diagonal corners of a cage. After being able to do this well, the possible reward locations changed to the other two diagonal corners. Genetically modified mice did the same as wild-type mice. In another task, after learning to alternate the two diagonal corners, only the location of a reward was changed. When mice were challenged to alternate randomly between these two tasks, wild-type mice were able to adapt quickly, but Suv39h2-deficient mice took much longer. “This serial investment learning task was essential,” says first author Shabeesh Balan. “Cognitive inflexibility is a basic symptom of ASD, and our new task was able to address this behavioral feature in a way that previous mouse studies could not.”
When the researchers examined what happened to the mouse brain when H3K9 methylation did not occur, they found that the experimental mice had activated important genes that are normally silenced during initial development. “Suv39h2 is known to be expressed in early neurological development and in H3K9 methylation,” explains Yoshikawa. “This keeps a check on the genes that should be turned off. But without it, the genes in the β-protocadherin cluster were abnormally expressed at high levels in embryos. mice“Because protocadherins are critical for the formation of neural circuits, researchers believe they have found an important biological pathway that could be central to various neurodevelopmental disorders.
The team then verified the importance of SUV39H2 in human ASD by finding that its expression was lower in the postmortem brain of people with ASD than in controls. “What started with a loss of function mutation in a single person with ASD,” says Yoshikawa, “has led to a general causal picture of ASD that culminates in a brain circuit abnormality.”
It has already been proposed that protocadherins are related to a wide range of mental disorders. This study demonstrates that SUV39H2 gene activation is a potential therapy for mental disorders, including ASD, that should be further investigated in future studies.
Shabeesh Balan et al, A variant of loss of function in SUV39H2 identified in autism spectrum disorder causes alteration of H3K9 trimethylation and deregulation of protocadherin β cluster genes in the developing brain. Molecular psychiatry (2021). DOI: 10.1038 / s41380-021-01199-7
Citation: SUV39H2: A Direct Genetic Link to Autism Spectrum Disorders (2021, July 19) Retrieved July 19, 2021 at https://medicalxpress.com/news/2021-07-suv39h2-genetic-link-autism -spectrum.html
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