Major Autism-Linked Gene Increases Accessibility of DNA During Development | Spectrum

In a dead end: Mice lacking the autism-linked POGZ gene altered the expression of DNAP, which is also implicated in autism.

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

People with a POGZ mutation are more likely than others to have autism and developmental disabilities. The POGZ protein binds to DNA and is thought to promote or suppress gene expression, but its exact function is unclear.

The new work identifies genes that are expressed differently in embryonic mice lacking POGZ, and it directs researchers to pathways potentially relevant for autism, says lead researcher John Rubenstein, professor of psychiatry at the University of California at San Francisco.

The results failed to replicate two studies from 2020 that found that POGZ regulates the production of new neurons in mice. But the gene could have multiple functions that change throughout development, says Sagiv Shifman, professor of genetics at the Hebrew University of Jerusalem in Israel, who led one of the previous studies but was not involved in it. new work.

Each study provides a snapshot of the role of the gene and captures only a small part of it – like trying to tinker with the proverbial image of an elephant after only seeing its tail or ear, says Shifman. “The system is very, very complex.

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

The researchers used a technique called “cut and execute” to identify 2,023 sites where the POGZ protein binds in the genome of embryonic wild-type mice. Of those sites, 92 percent were in regions where chromatin was accessible, and a disproportionate number overlapped enhancers – DNA bands that, when bound by a protein, encourage gene expression. Analysis showed that many genes close to POGZ binding sites improve chromatin accessibility and axon growth.

The team found that POGZ knockout mouse embryos had reduced expression of genes related to synapse formation and axon growth. Many of the most affected genes, including the SLITRK5 gene family, which are linked to Gilles de la Tourette syndrome and obsessive-compulsive disorder, cluster in the genome in accessible regions of chromatin. Without POGZ, the chromatin surrounding these genes became more compact, making the genes less accessible, according to the study.

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

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

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

IIn human and murine tissues, the researchers found that about half of POGZ’s binding sites also bind to ADNP – another protein linked to autism – and to HP1, which helps shape the structure of chromatin. .

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

Rubenstein and his colleagues suggest that POGZ and ADNP form a complex to do this. But these 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 POGZ’s role in neurodevelopment, it’s also unclear how POGZ alters the accessibility of genes in people with autism who don’t have a working copy of the gene. Rubenstein and his colleagues plan to investigate this matter.

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

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