January 10, 2022

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by: admin

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Tags: accessibility, Autismlinked, boosts, Development, DNA, gene, Spectrum, Top

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Categories: autism

Prime autism-linked gene boosts DNA accessibility throughout improvement | Spectrum

In a fix: mice lacking the autism-related gene POGZ have an altered expression of ADNP, which is also associated with autism.

The POGZ gene associated with autism, according to a new mouse study, facilitates the accessibility and expression of genes involved in wiring the brain in utero.

People with a mutation in POGZ are more likely to have autism and intellectual disabilities than those without. The POGZ protein binds to DNA and is believed to either promote or suppress gene expression, but its exact function is unclear.

The new work identifies genes that are differentially expressed in embryonic mice lacking POGZ and points researchers to potentially autism-related pathways, says lead researcher John Rubenstein, professor of psychiatry at the University of California, San Francisco.

The results failed to replicate two 2020 studies that found that POGZ regulated the production of new neurons in mice. But the gene could have multiple functions that change as it evolves, says Sagiv Shifman, a professor of genetics at the Hebrew University of Jerusalem in Israel who directed one of the earlier studies but was not involved in the new work.

Each study provides a snapshot of the gene’s role and only captures a small part – like trying to put together the proverbial picture of an elephant after seeing just its tail or ear, Shifman says. “The system is very, very complex.”

P.OGZ knockout mice die shortly before birth. But on embryonic day 13.5, the number of new neurons in the cortex is similar to that of wild-type mice, Rubenstein and his colleagues found.

Researchers used a technique called “cut and run” to identify 2,023 sites where the POGZ protein binds in the genome of wild-type embryonic mice. Of these sites, 92 percent were in regions of accessible chromatin, and a disproportionate number overlapped with enhancers – strips of DNA that, when bound to a protein, promote gene expression. Many genes near POGZ binding sites improve chromatin accessibility and axon growth, the analysis showed.

The team found that POGZ knockout mouse embryos had decreased the expression of genes related to synapse formation and axon growth. Many of the most severely affected genes, including the SLITRK5 family of genes associated with Tourette’s syndrome and obsessive-compulsive disorder, cluster in accessible chromatin regions in the genome. Without POGZ, the chromatin surrounding these genes became more densely packed, making the genes less accessible, the study shows.

“It appears that POGZ plays a very specific role in promoting the active state of chromatin and the transcription of a selected set of genes in the genome,” says study researcher Eirene Markenscoff-Papadimitriou, associate specialist in Rubenstein’s laboratory.

The knockout embryos also showed higher expression of the gene SLC6A1, which is strongly linked to autism and codes for a protein that transports the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) away from the synapses after its release.

POGZ appears to work similarly in the human brain: the protein binds to regions of DNA near the SLITRK gene family and other genes associated with autism, according to cut and run data from the human fetal cortex. The work was published in Cell Reports in December.

IThe researchers found that in both human and mouse tissue, about half of the binding sites of POGZ also bind to ADNP – another protein associated with autism – and HP1, which form the structure of chromatin.

“POGZ and ADNP appear to be working together to regulate the expression of other genes involved in neurodevelopment,” said Wendy Chung, a professor of pediatrics and medicine at Columbia University who was not involved in the work. (Chung is also director of clinical research at the Simons Foundation Autism Research Initiative, which, like Spectrum, is funded by the Simons Foundation.)

Rubenstein and his colleagues suspect that POGZ and ADNP form a complex for this. But those results are preliminary, warns Shifman. “We still have to understand exactly how the connection between POGZ and ADNP works.”

And while the new study helps explain the role of POGZ in neurodevelopment, it’s also unclear how POGZ alters the accessibility of genes in autistic people who lack a functional copy of the gene. Rubenstein and his colleagues want to investigate this next.

“It will be important to know if the mechanism is the same,” says Chung, in order to identify the continuing role of POGZ in the post-development of the human brain and what kind of treatment is possible.

Cite this article: https://doi.org/10.53053/MPVW6309

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