Gene Expression Signatures Indicate Loss of Function by Master Regulators of the Genome

RESEARCH SUMMARY

Study Title: Structural and functional properties of mSWI/SNF chromatin remodeling complexes revealed through single-cell perturbation screens

Publication: Molecular Cell, April 6, 2023, https://www.cell.com/molecular-cell/fulltext/S1097-2765(23)00203-4

Dana-Farber Cancer Institute authors: Cigall Kadoch, PhD; Jordan E. Otto; Evan B. Winter; Kristin Qian; Brittany C. Michel, PhD

Summary: 

Second only to the notorious TP53 gene, the genes for assemblages known as mSWI/SNF protein complexes are the most frequently mutated entities in cancer cells. Made up of 10-15 subunits, the complexes are built from the activity of 29 individual genes. The complexes play a key role in modifying chromatin – the twists of DNA and proteins that constitute chromosomes – so that genes become more or less active, switched on or switched off. Mutated forms of the genes responsible for mSWI/SNF complexes are found in more than 20% of human cancers. In some cases, it is the absence or alteration of one or more of the complexes' subunits that causes cancer. In a new study, scientists at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard used CRISPR-Cas9 technology to systematically stifle the roughly 29 genes associated with mSWI/SNF complexes, individually and in informative combinations in the context of a cancer cell. They tracked how each shutdown affected the structure and make-up of the complexes. The researchers then used the data to predict and identify, across thousands of human cancer gene expression profiles, which tumors harbor a mutation that results in a loss of mSWI/SNF function or which have gene expression patterns that mirror mSWI/SNF mutations. The findings may help doctors determine whether changes in this complex are playing important roles in a patient's cancer. Knowing these signatures, researchers aim to be better able to predict which tumors are likely to respond to the growing array of drug agents that target mSWI/SNF complexes in patients with cancer.

Impact:

Using advanced gene-silencing technology, researchers at Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard have systematically disabled the genes responsible for mSWF/SNF protein complexes, which play a key role in raising and lowering gene activity and which, in an abnormal form, are found in more than 20% of human cancers. The results enabled them to generate a series of gene expression signatures that may help researchers predict which patients with tumors may benefit from emerging drug agents that target these complexes.

Funding: This work was supported in part by awards from the National Institutes of Health; the American Cancer Society; the Pew-Stewart Scholars in Cancer Research; and the Klarman Cell Observatory.