PBRM1 will be the death of me. It is a beautiful but poorly behaved protein. We've spent years trying to pin down reliable phenotypes in renal cancer that relate to specific biochemical function and have been humbled again and again. We've found dozens of cell lines with no detectable PBRM1 knockout phenotype. Then we've defined a phenotype in one cell line only to find a completely different phenotype in a very similar cell line. Then to make things worse, we've identified a phenotype in a cell line, only to find that phenotype lost or completely reversed when we take the knockout cell line back out of storage.
While we all know by now that chromatin regulators have context-dependent function, we really need to pin down this context in order to figure out how PBRM1 acts as a tumor suppressor in renal cancer (and other cancers). So in this paper we went back to untransformed cells to define PBRM1's role in maintaining epithelial cell maintenance. To make a long story short (if you want the long version, it is all in the paper) we find that PBRM1 maintains the expression of stress response genes in epithelial cells. Under low stress conditions loss of PBRM1 is growth-promoting, but under high stress conditions PBRM1 is cytoprotective and is required for the induction of stress response genes, the reduction of reactive oxygen species, and, eventually the initiation of apoptotic pathways. Now that we've found this, we understand why the same cell line responds differently to PBRM1 loss depending on the cell culture conditions, and why cell lines with inherently high internal stress (oxidative stress or oncogene addition) are so sensitive to PBRM1 knockdown.
It's been a frustrating process, but a fruitful one (I think). Now we can start to piece together how PBRM1 responds to environmental signals to change gene expression. We have a lot of work to do, but I am hopeful that we have model that can explain all the varied and contradictory phenotypes reported for PBRM1.
"PBRM1 Regulates Stress Response in Epithelial Cells."
Libby is hooded and leaves the lab (sniff!). Libby is starting a postdoc in Ben Garcia's lab at UPenn and we are so happy for her! Congratulations!
Welcome to PULSe graduate student Surbhi Sood! She will be working on combining structural biology and genomics to decipher the connection between chromatin binding and transcriptional function of SWI/SNF chromatin remodelers. We are excited to get started!
A chemoproteomic portrait of the oncometabolite fumarate.
Aktan continues to be amazing. He received the PULSe graduate student in research award as well as a Bilsland Graduate Fellowship. He gave an amazing talk and is working hard on getting his many projects finished up.
Also pictured future lab member Surbhi with her poster award!!
Engagement of DNA and H3K27me3 by the CBX8 chromodomain drives chromatin association.
Libby did an amazing job defending her thesis. Congratulations Dr. Porter!
Several manuscripts we collaborated on are published!
The Musselman Lab
They published a nice manuscript characterizing the SANT1 domain of EZH2 using NMR. They find that it recognizes the the histone H4 N-terminal tail and that this binding is antagonized by various activating marks. "The EZH2 SANT1 domain is a histone reader providing sensitivity to the modification state of the H4 tail."
The Weake Lab
They characterized a cool new chiffon histone acetyltransferase (CHAT) complex unique to flies in: "The Drosophila Dbf4 ortholog Chiffon forms a complex with Gcn5 that is necessary for histone acetylation and viability."
Thanks for including us in your awesome science!
We are sad to see Jane leave, but happy that she gets to spend more time with family and hobbies. Jane set up the lab and kept everything running for many years. We appreciate everything you've done for us!
After 8 long years, our high throughput screen for BAF inhibitors is published! What a great collaborative effort with the Crabtree Lab, the Broad Institute and the amazing Mahmoudi Lab! These compounds inhibit just a subset of BAF function and serve as HIV latency reversal agents. There's still more to do in order to optimize, characterize and utilize these macrocycles, but we are excited that the first step is published.
Dykhuizen Lab News