IRIC - Institute for Research in Immunology and Cancer

Published on January 22, 2018

The human genome contains about 20,000 genes that encode the proteins that specify the structure and function of all tissues and organs in the body. Essential proteins are central to the structure of cells and tend to be mutated more frequently in disease. The understanding of these essential functions is critical to deciphering cancer and other diseases, as well as to understanding the complex networks of gene and protein interactions that allow cells to carry out the myriad processes needed for life.

While we have known which proteins are essential for cell proliferation and survival in simpler model organisms such as yeast, worms and flies for many years, this information has been lacking for human cells. Recent CRISPR/Cas9 technology has allowed the systematic interrogation of gene function in human cell lines. To interrogate genes essential for cell growth, proliferation and survival in human cells, the team of Dr. Mike Tyers, Principal Investigator at IRIC and Professor in the Department of Medicine at Université de Montréal, carried out a screen in a B-cell lymphoma line using a genome-wide CRISPR/Cas9 extended knockout library built by the group at IRIC. This library is the largest built to date and targets over 19,000 annotated genes as well as almost 4,000 additional hypothetical genes. As reported in a recent publication in the journal Molecular and Cellular Biology, the Tyers laboratory identified 2,280 essential genes, 234 of which were unique to the B-cell lymphoma line.

By comparisons to other published screens, the IRIC researchers found that gene/protein essentiality depends strongly on cell type. Less than 500 genes were essential in all cells, suggesting that this set of universal essentials is very much smaller than expected. Genes essential in more cell lines caused more severe fitness defects when mutated and encoded the evolutionarily conserved structural cores of protein complexes, whereas genes essential in fewer lines formed context-specific modules and encoded subunits at the periphery of essential complexes. This suggests that essential proteins evolved to form the very core functions of the cell and that non-essential proteins were then added to this core. The results also show that alternatively spliced regions of proteins tended to be non-essential and enriched for disordered proteins regions, consistent with addition of non-essential regulatory functions by splicing. Finally, this study found that at least 44 newly evolved hypothetical reading frames appeared to have important functions, suggesting that new genes can rapidly become essential in particular contexts.

Overall, these results illuminate the contextual nature and evolution of essential gene/protein functions in human cells. The Tyers group is now using the EKO library to chart the processes that control cell proliferation and to understand the precise mechanism of action of drugs and drug leads in cancer and other diseases.

To read the full article, visit: http://mcb.asm.org/content/early/2017/10/10/MCB.00302-17.abstract

Study cited
A high resolution genome-wide CRISPR/Cas9 viability screen reveals structural features and contextual diversity of the human cell-essential proteome

Bertomeu T, Coulombe-Huntington J, Chatr-aryamontri A, Bourdages KG, Coyaud E, Raught B, Xia B, Tyers M.

(2018) Mol Cell Biol, 38 pii: e00302-17

doi: 10.1128/MCB.00302-17