Top gene linked to autism increases DNA accessibility during development | Spectrum


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

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

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

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

The results failed to replicate two 2020 studies 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 Shifmana genetics professor at the Hebrew University of Jerusalem in Israel, who led one of the previous studies but was not involved in the new work.

Each study provides insight into the gene’s role and captures only a small part — like trying to cobble together the proverbial image of an elephant after seeing only its tail or ear, Shifman says. “The system is very, very complex.”

POGZ knockout mice die shortly before birth. But at 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.

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

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

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

Knockout embryos also had higher expression of the gene SLC6A1which is strongly linked to autism and codes for a protein that transports the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) away from synapses after its release.

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

IIn human and mouse tissues, the researchers found that about half of POGZ’s binding sites also bind ADNP – another autism-linked protein – and 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 studies. works. (Chung is also director of clinical research at the Simons Foundation Autism Research Initiative, which, like Spectrumis 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 have yet 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 gene accessibility in people with autism who don’t have a working copy of the gene. Rubenstein and his colleagues plan to investigate this next.

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

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