Nearly twenty years after the completion of the Human Genome Project, much of the genomic code remains a mystery. While many regions of the genome have been mapped to genes, large segments aren’t yet well understood. These segments may code for proteins whose significance has yet to be discovered.

Now a University of Texas Southwestern Medical Center cancer biologist is probing the depths of the unmapped genome to find the functional significance of overlooked proteins. Jin Chen was recruited in 2020 from the University of California San Francisco, where he was a postdoctoral fellow, with the help of a First-Time Tenure-Track Award from CPRIT.

In particular, Chen is studying so-called "microproteins," which may play roles in regulating cellular processes. "People traditionally had this arbitrary cutoff as to what a protein size should be," he says. "The cutoff was typically 100 amino acids; the proteins I’m looking at are 15 to 100 amino acids, on average around 50."

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Nearly twenty years after the completion of the Human Genome Project, much of the genomic code remains a mystery. While many regions of the genome have been mapped to genes, large segments aren’t yet well understood. These segments may code for proteins whose significance has yet to be discovered.

Now a University of Texas Southwestern Medical Center cancer biologist is probing the depths of the unmapped genome to find the functional significance of overlooked proteins. Jin Chen was recruited in 2020 from the University of California San Francisco, where he was a postdoctoral fellow, with the help of a First-Time Tenure-Track Award from CPRIT.

In particular, Chen is studying so-called "microproteins," which may play roles in regulating cellular processes. "People traditionally had this arbitrary cutoff as to what a protein size should be," he says. "The cutoff was typically 100 amino acids; the proteins I’m looking at are 15 to 100 amino acids, on average around 50."

These proteins may or may not have biological relevance, but to find out, Chen conducts large-scale screening tests for functional proteins. He uses CRISPR to knock out different specific sequences in millions of cells. Sequences that are essential to a cell’s functioning will cause the cell to die when they are knocked out. In a typical screen, Chen says he finds that about 10 percent, or a couple thousand, of the unannotated proteins he’s screening are functional.

Then he digs deeper, using biochemistry and genetics, to find out what their specific functions are, hoping to find microproteins crucial for cancer but not for normal cells.

In addition, in cancer, one cellular process that often goes awry is the translation of RNA to proteins. "It’s recently being more and more appreciated that translation is a very important checkpoint in cancer, and translation is often misregulated during tumorigenesis," he says. "This will help us understand what is being misregulated and help us develop interventions."

A protein that is essential for cancer cells, for example, but not for normal cells, might allow for a targeted therapy to be developed.

Chen uses cell lines from gastric cancer for his studies but plans to study a variety of cancers to see how gene regulation differs between different cancer types.

In his lab, he is continuing to develop new tools for studying the functional genome, including CRISPR-based techniques and large-scale functional screens. He finds the research environment at UT Southwestern conducive to collaborations that facilitate the translation of basic research, and says the potential for collaboration between other Texas institutions is high.

"The CPRIT award is vital because it really provides me with the resources and connections to start my lab," he says. "The generous support really allowed me to hire people and purchase equipment that will allow us to do more risky, high-reward, high risk science."

Chen was born and raised in Taiwan. He received his B.S. and M.S. in applied physics from Yale University and an M.S. in electrical engineering and Ph.D. in applied physics from Stanford University. He began a postdoctoral fellowship at UCSF in 2016.

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