The team of the Chinese Academy of Sciences has made new progress in autism research

The incidence of neurodevelopmental disorders, such as autism and ADHD in children, is increasing worldwide. Among them, the proportion of adolescents with autism in China is as high as 20%, and it is growing at a rate of 200,000 per year, seriously affecting family happiness.

Pattern diagram of POGZ inhibition of the 2C gene and reverse transcription transposable elements. Photo courtesy of interviewee

Genomic sequencing studies have shown that autism is a highly heterogeneous genetic developmental disorder. Depending on the individual’s genetic background, patients exhibit varying degrees of neurological dysfunction, such as intelligence, language, motor behavior defects, etc. However, due to the lack of in-depth understanding of the etiology of the disease, there is no effective clinical treatment. The team of Sun Yuhua, a researcher from the Institute of Aquatic Sciences of the Chinese Academy of Sciences, revealed that the autism-related protein POGZ inhibits the 2C gene and reverse transcription transposable element, and the relevant results were recently published in Cell Reports.

According to experts, endogenous retroviruses are a type of transposon derived from retroviruses that infected host cells hundreds of millions of years ago. In some special cases, retroviruses invade the host’s germ cells and then pass on to offspring along with the germ cells. After millions of years of evolution, the retrovirus evolved into ERV, which survived in the genome. For a long time, ERV was considered a junk sequence on the genome, silent under the action of host epigenetic mechanisms. However, recent studies have shown that ERVs exhibit dynamic changes in the early stages of embryonic development and have important functions in embryonic development.

For example, after the sperm combines with the egg to form a fertilized egg, it develops to the 2-cell stage through cleavage and begins to activate the zygotic genome, and the activated transcript includes the endogenous retrovirus MERVL. Under normal physiological conditions, the expression of ERV is subject to strict time conditioning knots. Abnormal activation of ERV due to genetic or environmental factors can have serious consequences. Notably, abnormal activation of ERV is strongly associated with the onset and progression of neurodevelopmental disorders.

POGZ is one of the most frequently mutated autism susceptibility genes, encoding a transcription factor in various functional domains such as zinc-containing finger, centromerin B-DNA binding domain, and transposase-derived DDE. Previous studies have found that POGZ protein, as a chromatin regulator, plays an important role in maintaining the stability of embryonic stem cells. However, its specific mechanism of action remains unclear. The team of Sun Yuhua from the Institute of Hydrobiology, Chinese Academy of Sciences, used mouse embryonic stem cells as a model to reveal the key role of POGZ in the maintenance of embryonic stem cell stability, neurodevelopment and disease occurrence by regulating endogenous retroviruses.

The study found that the expression of 2-cell phase related genes was significantly upregulated in POGZ-deleted embryonic stem cells, and the expression of about 50 ERVs (IAPEY, IAPEZ, etc.) was abnormally upregulated by POGZ deletion, suggesting that POGZ inhibited the expression of these 2C genes and repetitive sequences at the transcriptional level. Importantly, during the neural induction differentiation of embryonic stem cells, POGZ deletion leads to disturbance in the expression of neurodevelopmental genes and defects in the formation of neural precursor cells, accompanied by abnormal activation of IAPEY elements.

On the one hand, POGZ directly binds to and inhibits the expression of Dux, a key gene in the 2C cell stage. On the other hand, by interacting with SETDB1 and TRIM28 in the heterochromatin machine complex, they are recruited to catalyze and maintain inhibitory histone modifications H3K9me3, leaving ERVs in a silent state. After POGZ deletion, ERV forms chimeric transcripts with neighboring genes and is in a state of abnormal activation. In view of the close relationship between abnormal activation of ERV and neurodevelopmental disorders, the research results provide a new important theoretical basis for the pathogenesis of POGZ mutations and new ideas for the development of drugs for the treatment of related diseases. (Source: China Science News, Li Sihui, Sun Hui)

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