TrxG proteins in development and disease

In knockout mouse studies, developmental phenotypes of TrxG loss-of-function range from early embryonic lethality to later or milder defects, depending on the targeted component. However, both SWI/SNF and COMPASS complexes are required for normal development¹.

In line with their importance for maintaining gene expression patterns and cell identity, many TrxG proteins show deregulation in cancer. Check out the full guide for more details.

Therapeutic targeting of TrxG proteins

Due to their frequent misregulation or mutation in human cancers, several compounds targeting TrxG proteins are in preclinical or clinical development. These include small-molecule inhibitors disrupting the WDR5-MLL interaction, thus inhibiting the function of COMPASS-like complexes, and several molecules targeting various SWI/SNF components. Given the described dependencies between SWI/SNF-mutated tumors and PRC2 inhibition, the development of novel drugs targeting SWI/SNF components may provide exciting opportunities for combination treatment in cancers with loss-of-function PRC2 mutations^1,2.

References

1. Piunti, A., Shilatifard, A. Epigenetic balance of gene expression by Polycomb and COMPASS families Science 352 , (2016)
2. Bracken, A. P., Brien, G. L., Verrijzer, C. P. Dangerous liaisons: interplay between SWI/SNF, NuRD, and Polycomb in chromatin regulation and cancer Genes Dev 33 ,936-959 (2019)