Drier et al. describe how enhancer hijacking rewires the regulation of the oncogenic transcription factor MYB and drives adenoid cystic carcinoma. Translocation of MYB near super-enhancers that are themselves bound by MYB creates a vicious cycle where MYB drives its own transcription. MYB also binds enhancers that drive different regulatory programs in alternate cell lineages in ACC, cooperating with TP63 in myoepithelial cells and a Notch program in luminal epithelial cells. Additional genetic hits to the Notch pathway activate Notch signaling and shift the epigenetic balance between myoepithelial and luminal cells to luminal only high grade ACC. Bromodomain inhibitors that block enhancer function slow tumor growth of low-grade ACC xenografts models in vivo.
- MYB rearrangements often retain intact MYB transcript, translocating it to the NFIB locus or other loci rich in strong enhancers.
- The translocated enhancers are driven by MYB binding, yielding oncogenic positive feedback loop driving very high levels of MYB.
- MYB overexpression support tumorgenicity of both myoepithelial cells and luminal cells in adenoid cystic carcinoma, where MYB cooperates with TP63 in myoepithelial cells and support Notch signaling in luminal cells.
- Genetic hits to the Notch pathways shift the epigenetic balance toward luminal cells only, yielding high-grade aggressive adenoid cystic carcinoma.
- The bromodomain inhibitor JQ1, known to block enhancer function and specifically super-enhancer function inhibit growth of lower grade adenoid cystic carcinoma in mice xenografts.
Drier Y, Cotton MJ, Williamson KE, Gillespie SM, Ryan RJ, Kluk MJ, Carey CD, Rodig SJ, Sholl LM, Afrogheh AH, Faquin WC, Queimado L, Qi J, Wick MJ, El-Naggar AK, Bradner JE, Moskaluk CA, Aster JC, Knoechel B, Bernstein BE. Nature Genetics 2016 Mar;48(3):265-72.
Will Flavahan, Yotam Drier, et al. demonstrate that hypermethylation-induced loss of genomic insulator function causes the development of oncogenic genome topology configurations in IDH1-mutant glioma. This topological restructuring allows a constitutive housekeeping enhancer to interact with and drive the potent glioma oncogene PDGFRA.
-The hypermethylator phenotype observed in IDH1-mutant glioma extends to CpGs present in the binding sites of the methylation-sensitive insulator protein, CTCF, leading to loss of key insulators in these cells.
-Loss of an insulator protecting PDGFRA results in oncogene activation and tumor progression.
-Treatment of IDH1 mutant cells with the DNMT inhibitor 5-azacytidine allowed restoration of insulator function and silencing of PDGFRA.
-CRISPR deletion of insulators in IDH1 wild type glioma cells activated PDGFRA expression and increased cellular proliferation in a PDGFRA-dependent manner.
Insulator dysfunction and oncogene activation in IDH mutant gliomas.
Flavahan WA*, Drier Y*, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suvà ML, Bernstein BE. Nature. 2016 Jan 7;529(7584):110-4. doi: 10.1038/nature16490.
van Galen et al. introduce Mint-ChIP, an approach for multiplexed ChIP-seq on small cell numbers. The approach allows quantitative comparisons of global and locus-specific histone modification levels. The technology is demonstrated by mapping hematopoietic stem cell chromatin landscapes and quantifying changes in leukemia cells treated with epigenetic inhibitors. Detailed protocol now available on the Resources page.
– Mint-ChIP enables highly multiplexed ChIP-seq on low-input samples
– Quantitative precision is achieved by normalizing histone modifications to total H3
– Active and repressed regions are mapped in human hematopoietic stem cells
van Galen, Peter et al. Molecular Cell.
Russell Ryan and Yotam Drier describe PEAR-ChIP, a novel approach for the detection of genomic rearrangements associated with acetylated chromatin. The authors apply this technology to patient samples from several distinct subtypes of B cell lymphoma, revealing therapeutically targetable rearrangements, and uncovering novel mechanisms by which the oncogenes MYC and BCL6 are regulated via native and rearranged enhancers.
- PEAR-ChIP allows for genome-wide enhancer activity and rearrangement detection in a single protocol
- PEAR-ChIP analysis of mantle cell lymphoma, diffuse large B cell lymphoma, and chronic lymphocytic leukemia reveals “enhancer hijacking”, enhancer amplification, gene fusion, and inactivating rearrangements affecting numerous cancer genes, including CCND1, BCL2, MYC, BCL6, PDCD1LG2, CIITA, and others.
- Lymphoma subtype-specific MYC enhancers are active in lymphomas lacking MYC rearrangements, and are associated with SNPs linked to inherited lymphoma risk.
- Germinal center-specific BCL6 enhancers are activated by the oncogenic transcription factor MEF2B, and can activate MYC via enhancer hijacking in a “pseudo-double-hit” t(3;8)(q27;q24) rearrangement.
Ryan RJ, Drier Y, Whitton H, Cotton MJ, Kaur J, Issner R, Gillespie S, Epstein CB, Nardi V, Sohani AR, Hochberg EP, Bernstein BE. Cancer Discov. 2015 Jul 30. pii: CD-15-0370.
Dylan joins us as a new Research Assistant, Sara joins us as a new PhD student, while Sarah, Sid and Anuraag join us as new postdoctoral fellows. Welcome all!
Happy Holidays from the Bernstein lab and friends!
Laura joins us as the new Lab Manager.
Peter joins us from John Dick’s lab at the University of Toronto.
Will is coming to us from Jeremy Rich’s lab at the Cleveland Clinic.
Anoop Patel, Mario Suvà, Shawn Gillespie with Itay Tirosh from the Regev lab and co-authors have described in new detail tumor heterogeneity in primary glioblastoma. The study, published this week in Science, shows the diverse set of transcriptional profiles that are present in primary tumors.
The Boston Globe featured the study and brings it to a point:
“This may be to my knowledge the first study that tried to do this carefully within individual cells from human tumors and it is a bummer, because this is why cancer is so hard to cure,” said Sean Morrison, director of the Children’s Medical Center Research Institute at the University of Texas Southwestern. “It’s a different battle in every patient in some ways. And this heterogeneity is why the best ideas we often have will kill 90 percent of the cells and leave the other 10 percent behind.”
Read the full paper here:
Anoop P. Patel, Itay Tirosh, John J. Trombetta, Alex K. Shalek, Shawn M. Gillespie, Hiroaki Wakimoto, Daniel P. Cahill, Brian V. Nahed, William T. Curry, Robert L. Martuza, David N. Louis, Orit Rozenblatt-Rosen, Mario L. Suvà, Aviv Regev, and Bradley E. Bernstein. (2014). Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science . doi:10.1126/science.1254257
Mario Suvà, Esther Rheinbay, Shawn Gillespie, and Anoop Patel from this lab and colleagues have discovered a set of key transcription factors underlying glioblastoma stem-like cells.
From the Broad blog:
Glioblastoma, the most common and most aggressive form of brain cancer in adults, remains effectively incurable. Evidence suggests that “stem-like” cells help drive this difficult-to-treat disease. These cells may possess properties that give them the ability to resist treatment and drive cancer’s growth, but pinpointing them and understanding the circuitry that makes them behave the way they do has been a major challenge.
Now, through the lens of epigenomics, researchers are gaining a clearer picture of the core set of switches that can turn a cancer cell into an aggressive glioblastoma stem cell capable of driving a tumor’s growth. Instead of focusing on genetics, the research team has found that by flipping epigenetic switches that alter gene activity, they can control a tumor cell’s aggressive behavior by making it regress into a stem-cell-like state.
“The code is fairly simple,” says Mario Suvà, a Broad associated scientist and a faculty member at Massachusetts General Hospital. “It’s a difference of four transcription factors: that’s all it takes to switch from a non-aggressive brain tumor cell to a very aggressive brain tumor cell.”
Read the full paper in Cell: Suvà M et al. “Reconstructing and reprogramming the tumor propagating potential of glioblastoma stem-like cells.” Cell April 10, 2014. DOI: 10.1016/j.cell.2014.02.030.