Genetic Determinants of Translation in Humans
Postdoctoral Fellow, Genetics
March 8, 2018
Foege N130A, Wallace H. Coulter Seminar Room
Translation efficiency, i.e. the number of proteins synthesized per transcript, contributes significantly to determining protein levels, yet little is currently known about the genetic determinants of translation efficiency in humans or their relevance to disease. For Dr. Cenik’s postdoctoral work at Stanford, he has focused on addressing this problem. Can has generated RNA-Seq and ribosome profiling data from a diverse set of individuals and integrating these measurements with quantitative mass spectrometry-based proteomics. This study revealed that translation efficiency indeed varies among individuals and that the genetic factors underlying this translational variability can be mapped. In several cases, his research has pinpointed the mechanisms controlling the observed variation in translation efficiency, with genetic variability in sequences near the translation initiation sites being one such example. Can recently extended these findings by searching for disease-relevant genetic differences that may underlie changes in translation. Specifically, he analyzed ~4700 cancer exome sequencing datasets from 21 cancer types. Strikingly, ~18% of all bladder cancer patients harbor somatic mutations that alter the sequences surrounding the translation initiation site in one such gene, TBC1D12. As such, these mutations constitute one of the most common noncoding cancer mutations identified to date.
Dr. Cenik’s current unpublished work involves the development of new assays and computational infrastructure to further characterize both cis- and trans- regulators of translation in humans. Specifically, he has undertaken an interdisciplinary approach that establishes the feasibility of interrogating translation landscape from as few as 1000 cells, a three order of magnitude improvement over existing methods. Specifically, his lab designed and built a custom microfluidic chip that enabled them to simultaneously purify and select RNA fragments protected by ribosomes (17-35nt) using isotachophoresis from cell lysates. His research aims to further improve this method to enable the transcriptome-wide measurement of ribosome occupancy from single cells. In addition, his group is using CRISPR-based functional genomic screens to discover new translation regulatory proteins important for cellular homeostasis. The crux of these screens is a novel assay that he recently developed for quantification of single cell global protein synthesis and polyA mRNA content. These studies will pinpoint a critically missing dimension of gene expression regulation by developing a toolbox of single cell translation assays for comprehensive characterization of translation control elements.
Can Cenik is currently a postdoctoral fellow in Dr. Michael Snyder’s laboratory at Stanford Medical School. He received his undergraduate degree magna cum laude in applied mathematics with highest honors from Harvard College. He was the recipient of the Thomas Temple Hoopes `19 Prize, annually given to the most outstanding research theses. For his graduate studies, he applied computational methods to characterize human 5’UTR introns and their role in a novel mRNA export pathway in Dr. Frederick Roth’s laboratory at Harvard Medical School. His research is currently supported by the NIH Pathway to Independence Award (K99/R00).