The Chan Zuckerberg Initiative (CZI) has awarded a pilot grant for a collaboration between principal investigators Neville Sanjana, PhD, Core Faculty Member at the New York Genome Center (NYGC), Associate Professor in the Department of Biology at New York University (NYU) and Associate Professor of Neuroscience and Physiology at the NYU School of Medicine, and Eric Lai, PhD, Member of the Developmental Biology Program of Sloan Kettering Institute (SKI) and Affiliate Member of the NYGC. The grant supports Dr. Sanjana and Dr. Lai’s work to study the impact of neuron-specific gene variants on neurodegenerative diseases.
Many genes are active only in specific kinds of cells, like muscle, skin, or neurons. However, many other genes are deployed across multiple settings, but the version can be different from celltype to celltype. Notably, neurons are especially proficient at making distinct “remixes” of thousands of genes, also known as “isoforms”.
L to R: Dr. Neville Sanjana and Dr. Eric Lai
“Neurons have an incredibly diverse repertoire of how they express genes — much more than other types of cells in the body. Our work is aimed at understanding the significance of this genetic diversity and how it impacts healthy and aging brains,” said Dr. Sanjana. “However, there are both challenges and opportunities to decipher these neural codes,” said Dr. Lai. “We don’t fully understand how all these neural isoforms are made, or what they do.”
Drs. Sanjana and Lai aim to answer these questions by combining their expertise in neural transcriptomes and RNA-targeting CRISPRs.
Dr. Lai’s lab studies multiple strategies that enable neurons to make distinct isoforms. A prominent category includes alternative splicing, which often changes what kind of protein is encoded by an RNA. Another unusual “remix” is circular RNA. While most RNA products are linear, some RNAs form enigmatic RNA circles, which are particularly abundant in neurons. A third program involves the end of RNAs, termed the 3’ untranslated region (3’ UTR). Neurons globally implement longer 3’ UTRs, which rewire the landscape of regulatory programs acting on RNA. However, while neurons specifically express thousands of splice isoforms, circular RNAs, and extended 3′ UTRs, we know little about their individual biological functions. Nevertheless, all of these isoform programs are changed in aging and neurodegeneration, and clearly deserve attention.
New technologies developed in Dr. Sanjana’s group now enable comprehensive studies of the roles of RNA isoforms. Dr. Sanjana and his labs at NYGC and NYU pioneered the use of RNA-targeting CRISPR for massively-parallel screens of human transcriptomes. Their CRISPR-based technology provides a new way to target specific gene isoforms. Together, the teams will apply this to stem cell-derived human cortical neurons, to study how each RNA isoform might be involved in neurodegenerative diseases.
The work funded by the pilot grant will capitalize on RNA-targeting CRISPRs to study the role of transcript diversity in neurons, which may provide avenues to intervene with neurodegenerative diseases. “We are grateful for CZI support to bring our teams together for this new and timely collaborative project,” said Dr. Lai. “We hope to pinpoint key RNAs that influence neurodegeneration in human cortical neurons and, using this new kind of dataset, find new therapeutic targets,” said Dr. Sanjana.
About the New York Genome Center
The New York Genome Center (NYGC) is an independent, nonprofit academic research institution that serves as a multi-institutional hub for collaborative genomic research. Leveraging our strengths in technology development, computational biology, and whole genome sequencing, our mission is to advance genomic science and its application to novel biomedical discoveries. NYGC’s areas of focus include the development of computational and experimental genomic methods and disease-focused research to advance the understanding of the genetic basis of cancer, neurodegenerative disease, and neuropsychiatric disease. We are committed to prioritizing diversity, equity, and inclusion, which is fundamental to promoting greater collaboration, innovation, and discovery. www.nygenome.org
