A team led by researchers from UCLA and the University of Pennsylvania has produced a first-of-its-kind catalog of gene-isoform variation in the developing human brain. This new dataset provides crucial insights into the molecular basis of neurodevelopmental and psychiatric brain disorders and paves the way for targeted therapies.
DNA – illustrative photo. Image credit: Pixabay (Free Pixabay license)
The research, published in Science, also details how the expression of transcripts varies by cell type and maturity, finding that changing the expression levels of genetic isoforms can help us better understand how the human brain develops.
Every cell in our body contains the same genetic information encoded in DNA, but it is the expression of different proteins, encoded in mRNA transcripts, that give cells their distinct functions. These varied proteins, or isoforms, mostly arise from alternative splicing – a process that is widespread in the brain and contributes to its wide range of proteins and characteristics.
“We knew, based on our previous research, that isoform regulation is a key molecular feature for understanding brain development and genetic risk for neuropsychiatric disorders,” said Dr. Luis de la Torre-Ubieta du Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at UCLA, who co-led the study alongside Dr. Michael Gandal, associate professor of psychiatry and genetics at the Perelman School of Medicine at the University of Pennsylvania .
Previously, despite its prevalence, the role of cell type-specific splicing and transcription isoform diversity in the developing human brain had not been systematically studied due to limitations of previous generations of sequencing technologies . Here, researchers were able to leverage new third-generation long-read sequencing technologies to capture full-length RNA molecules and profile the complete transcriptome of two major regions of the developing neocortex: the germinal zone, which contains stem cells, and the cortical zone. plate, which houses the newly generated neurons.
This technology allowed researchers to discover 214,516 unique isoforms, more than 70% of which had never been studied before. They then compared the two regions of the developing brain and observed that changes in isoform expression levels are important for neurogenesis, differentiation and cell fate – essentially brain maturation.
Researchers have discovered thousands of isoform changes that occur during brain development, implicating previously uncharacterized RNA-binding proteins in cell identity and cell fate decisions. Their findings also elucidate genetic risk mechanisms for neurodevelopmental and neuropsychiatric disorders, including a reassessment of the importance and clinical relevance of thousands of rare genetic variants.
“We found that genes at high risk for autism or neurodevelopmental disorders tend to be genes that have more isoforms, and these isoforms are expressed differently during neurogenesis,” de la Torre said. -Ubieta, assistant professor of psychiatry and behavioral sciences. “This implies that dysregulation of the expression of specific isoforms is a potential mechanism underlying these disorders. »
Scientists who study the brain often rely on publicly available catalogs of genes and gene transcripts. However, human brain tissues, especially embryonic tissues, are difficult to access, limiting the completeness of these datasets. For this study, researchers obtained six developing human neocortex tissue samples representing the mid-gestation period, or 15 to 17 weeks after conception. This moment in human brain development constitutes a critical window during which the complexity of our brain – the most sophisticated organ in our body – begins to emerge.
“These tissue samples enabled a striking level of discovery of new transcripts,” Gandal said. “And because these databases have not incorporated or represented these critical times, we can significantly expand our understanding of how genes are regulated in the context of human brain development.” »
The study results have strong therapeutic implications and could be clinically actionable, the researchers said. The discovery of new transcripts could pave the way for the identification of new therapeutic approaches in the context of gene therapy trials or targeted therapeutic trials for individuals carrying rare mutations associated with psychiatric or neurodevelopmental disorders.
In the shorter term, the data will also have direct implications in improving our ability to make genetic diagnoses of neurodevelopmental disorders. Because the study revealed several thousand genetic variants that are more impactful than previously thought, families or individuals carrying these variants can better understand how their children might be predisposed to certain disorders.
Gandal shared the dataset with several colleagues at Children’s Hospital of Philadelphia, which has a large population of children with rare neurodevelopmental disorders or undiagnosed developmental disorders. Doctors are already using this resource to better interpret neurogenetics diagnostically.
“I’m really excited to leverage this resource to help patients,” said Gandal, who is also a practicing psychiatrist. “This knowledge brings us closer to being able to develop targeted treatments and understand genetic mechanisms in a much more specific way. »
Other UCLA authors include Ashok Patowary, Pan Zhang, Celine K. Vuong, Xinzhou Ge, Kangcheng Hou, Minsoo Kim, Michael Margolis, Bogdan Pasaniuc and Jingyi Jessica Li. Connor Jops, Naihua Gong, Daniel Vo, Xusheng Wang and Chunyu Liu contributed to this study.
The research was supported by the Simons Foundation Autism Research Initiative, the National Institute of Mental Health, the National Science Foundation and the UCLA Medical Scientist Training Program.
Source: UCLA
Originally published in The European Times.
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