Featured Publications

 
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Chromatin landscapes reveal developmentally encoded transcriptional states that define human glioblastoma (mack et al., 2019 Journal of Experimental Medicine)

Glioblastoma (GBM) remains today an incurable and highly aggressive brain tumor. Large consortia based efforts have sought to define, dissect, and catalogue the landscape of mutations of GBM, with the goal of pairing mutated cancer genes with therapeutic targets. Unlike other cancers, these approaches have failed to reveal actionable targets for therapy in GBM; thus calling for alternative strategies to discover new drugs. Here, we mapped active chromatin landscapes with gene expression, whole-exomes, copy number profiles, and DNA methylomes across 44 glioblastoma stem cell (GSCs) models, 50 primary tumors, and 10 neural stem cells (NSCs) to identify essential super enhancer (SE)-associated genes and the core transcription factors (TFs) that establish SEs and maintain GSC identity. We show that GSCs segregate into two groups dominated by distinct enhancer profiles and unique developmental core TF regulatory programs. Group specific TFs enforce GSC identity — they exhibit higher activity in GBM versus normal NSCs, are associated with poor clinical outcomes, and are required for GBM growth in vivo. Although TFs are commonly considered undruggable, we show that group specific enhancer regulation of the MAPK/ERK pathway predicts sensitivity to MEK inhibition. These data demonstrate that transcriptional identity can be leveraged to identify novel dependencies and therapeutic approaches.

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Development of a Selective CDK7 Covalent Inhibitor Reveals Predominant Cell-Cycle Phenotype (olson et al., 2019 cell chemical biology)

Cyclin-dependent kinase 7 (CDK7) is a key regulator of both the cell cycle and transcription, but its precise role remains uncertain. THZ1, a CDK7 inhibitor, was previously shown to strongly inhibit superenhancer-associated gene expression. However, potent CDK12/13 off-target activity obscured CDK7’s contribution to the initially observed phenotype. Here, we characterize a newly discovered, more selective covalent inhibitor of CDK7 in YKL-5-124. Treatment with this compound induces G1 arrest and inhibits E2F-driven cell cycle genes, phenotypes which are furthermore rescued by a CDK7 mutant which renders resistance to engagement by YKL-5-124. Unlike THZ1, treatment with YKL-5-124 resulted in no change to RNA polymerase II CTD phosphorylation. Concurrent treatment with YKL-5-124 and THZ531, a selective CDK12/13 inhibitor, was able to phenocopy THZ1. These findings highlight the importance of CDK7/12/13 polypharmacology for the anti-cancer activity of THZ1 and posits that CDK7 inhibition may be useful in the treatment of cancers characterized by E2F misregulation.

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Small-molecule targeting of brachyury transcription factor addiction in chordoma (Sharifnia et al., 2019 Nature medicine)

Chordoma is a primary bone cancer with no approved therapy. Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In chordoma, we find that T is associated with a 1.5-Mb region containing a cluster of super enhancers and is the most highly expressed super-enhancer associated transcription factor. Transcriptional CDK inhibition leads to preferential downregulation of brachyury protein levels in all models tested, and, in vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers.

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Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma (Zeid et al., 2018 Nature Genetics)

Neuroblastoma is one of the most frequent pediatric solid tumors. Amplification of the transcription factor MYCN is the central hallmark of high-risk disease and results in excess levels of the protein in the nucleus where it can bind many thousands of regions the genome. Here we show that when amplified, oncogenic MYCN begins to invade tissue specific enhancers where it reshapes the neuroblastoma gene expression program in collaboration with tissue specific transcription factors like TWIST1. This axis of enhancer regulated genes correlates with poor survival and is dependent on tissue specific transcription factor activity creating an avenue to selectively target the activity of oncogenic MYCN.

Medulloblastoma origins (Lin et al., 2016 Nature)

In this collaboration with St. Jude's and the German cancer research center (DKFZ), we mapped active enhancer landscapes across all four known medulloblastoma subtypes. In many developmental models including embryonic stem cells, large clustered enhancer elements (super-enhancers or SEs) regulate key lineage specifying transcription factors that in turn bind and regulate other lineage transcription factors through enhancers. We hypothesized and showed that an inference of transcription factor connectivity learned through analyzing subtype specific enhancer landscapes could reveal key subtype specific lineage master regulators. We identified a subset of transcription factors (HLX, EOMES, LHX2, and LMX1A) that delineate the Group3/Group4 regulatory axis. Lineage tracing of these factors identified spatiotemporal restricted expression in the nuclear transitory zone, an assembly point for immature deep cerebellar nuclei. Deletion of LMX1A, a Group4 specific factor, in mice causes developmental defects in the developing cerebellum in this region and reductions in expression for other Group4 genes. This approach establishes a framework for the inference of tumor cell of origin mapping through the analysis of enhancer regulator landscapes.

For the most up to date list of publications click here

1. Saint-André V, Federation AJ, Lin CY, Abraham BJ, Reddy J, Lee TI, Bradner JE,
Young RA. Models of human core transcriptional regulatory circuitries. Genome
research. 2016; 26(3):385-96. PubMed [journal] PMID: 26843070, PMCID: PMC4772020

2. Lin CY, Erkek S, Tong Y, Yin L, Federation AJ, Zapatka M, Haldipur P, Kawauchi D,
Risch T, Warnatz HJ, Worst BC, Ju B, Orr BA, Zeid R, Polaski DR, Segura-Wang M,
Waszak SM, Jones DT, Kool M, Hovestadt V, Buchhalter I, Sieber L, Johann P,
Chavez L, Gröschel S, Ryzhova M, Korshunov A, Chen W, Chizhikov VV, Millen KJ,
Amstislavskiy V, Lehrach H, Yaspo ML, Eils R, Lichter P, Korbel JO, Pfister SM,
Bradner JE, Northcott PA. Active medulloblastoma enhancers reveal
subgroup-specific cellular origins. Nature. 2016; 530(7588):57-62. PubMed
[journal] PMID: 26814967

3. Heyn H, Vidal E, Ferreira HJ, Vizoso M, Sayols S, Gomez A, Moran S, Boque-Sastre
R, Guil S, Martinez-Cardus A, Lin CY, Royo R, Sanchez-Mut JV, Martinez R, Gut M, 
Torrents D, Orozco M, Gut I, Young RA, Esteller M. Epigenomic analysis detects
aberrant super-enhancer DNA methylation in human cancer. Genome biology. 2016;
17:11. PubMed [journal] PMID: 26813288, PMCID: PMC4728783

4. Shu S, Lin CY, He HH, Witwicki RM, Tabassum DP, Roberts JM, Janiszewska M, Huh
SJ, Liang Y, Ryan J, Doherty E, Mohammed H, Guo H, Stover DG, Ekram MB, Peluffo
G, Brown J, D'Santos C, Krop IE, Dillon D, McKeown M, Ott C, Qi J, Ni M, Rao PK, 
Duarte M, Wu SY, Chiang CM, Anders L, Young RA, Winer EP, Letai A, Barry WT,
Carroll JS, Long HW, Brown M, Liu XS, Meyer CA, Bradner JE, Polyak K. Response
and resistance to BET bromodomain inhibitors in triple-negative breast cancer.
Nature. 2016; 529(7586):413-7. NIHMSID: NIHMS742790 PubMed [journal] PMID:
26735014, PMCID: PMC4854653

5. Nabet B, Ó Broin P, Reyes JM, Shieh K, Lin CY, Will CM, Popovic R, Ezponda T,
Bradner JE, Golden AA, Licht JD. Deregulation of the Ras-Erk Signaling Axis
Modulates the Enhancer Landscape. Cell reports. 2015; 12(8):1300-13. NIHMSID:
NIHMS711801 PubMed [journal] PMID: 26279576, PMCID: PMC4551578

6. Hnisz D, Schuijers J, Lin CY, Weintraub AS, Abraham BJ, Lee TI, Bradner JE, Young
RA. Convergence of developmental and oncogenic signaling pathways at
transcriptional super-enhancers. Molecular cell. 2015; 58(2):362-70. NIHMSID:
NIHMS664562 PubMed [journal] PMID: 25801169, PMCID: PMC4402134

7. Wolf E, Lin CY, Eilers M, Levens DL. Taming of the beast: shaping Myc-dependent
amplification. Trends in cell biology. 2015; 25(4):241-8. NIHMSID: NIHMS646176
PubMed [journal] PMID: 25475704, PMCID: PMC4380620

8. Brown JD, Lin CY, Duan Q, Griffin G, Federation AJ, Paranal RM, Bair S, Newton G,
Lichtman AH, Kung AL, Yang T, Wang H, Luscinskas FW, Croce KJ, Bradner JE,
Plutzky J. NF-κB directs dynamic super enhancer formation in inflammation and
atherogenesis. Molecular cell. 2014; 56(2):219-31. NIHMSID: NIHMS632852 PubMed
[journal] PMID: 25263595, PMCID: PMC4224636

9. Lane AA, Chapuy B, Lin CY, Tivey T, Li H, Townsend EC, van Bodegom D, Day TA, Wu
SC, Liu H, Yoda A, Alexe G, Schinzel AC, Sullivan TJ, Malinge S, Taylor JE,
Stegmaier K, Jaffe JD, Bustin M, te Kronnie G, Izraeli S, Harris MH, Stevenson
KE, Neuberg D, Silverman LB, Sallan SE, Bradner JE, Hahn WC, Crispino JD, Pellman
D, Weinstock DM. Triplication of a 21q22 region contributes to B cell
transformation through HMGN1 overexpression and loss of histone H3 Lys27
trimethylation. Nature genetics. 2014; 46(6):618-23. NIHMSID: NIHMS575620 PubMed
[journal] PMID: 24747640, PMCID: PMC4040006

10. Chapuy B, McKeown MR, Lin CY, Monti S, Roemer MG, Qi J, Rahl PB, Sun HH, Yeda KT,
Doench JG, Reichert E, Kung AL, Rodig SJ, Young RA, Shipp MA, Bradner JE.
Discovery and characterization of super-enhancer-associated dependencies in
diffuse large B cell lymphoma. Cancer cell. 2013; 24(6):777-90. NIHMSID:
NIHMS545066 PubMed [journal] PMID: 24332044, PMCID: PMC4018722

11. Anand P, Brown JD, Lin CY, Qi J, Zhang R, Artero PC, Alaiti MA, Bullard J, Alazem
K, Margulies KB, Cappola TP, Lemieux M, Plutzky J, Bradner JE, Haldar SM. BET
bromodomains mediate transcriptional pause release in heart failure. Cell. 2013; 
154(3):569-82. NIHMSID: NIHMS538740 PubMed [journal] PMID: 23911322, PMCID:
PMC4090947

12. Ji X, Zhou Y, Pandit S, Huang J, Li H, Lin CY, Xiao R, Burge CB, Fu XD. SR
proteins collaborate with 7SK and promoter-associated nascent RNA to release
paused polymerase. Cell. 2013; 153(4):855-68. NIHMSID: NIHMS599492 PubMed
[journal] PMID: 23663783, PMCID: PMC4103662

13. Lovén J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, Young
RA. Selective inhibition of tumor oncogenes by disruption of super-enhancers.
Cell. 2013; 153(2):320-34. NIHMSID: NIHMS462455 PubMed [journal] PMID: 23582323, 
PMCID: PMC3760967

14. Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, Rahl PB, Lee TI,
Young RA. Master transcription factors and mediator establish super-enhancers at
key cell identity genes. Cell. 2013; 153(2):307-19. NIHMSID: NIHMS465689 PubMed
[journal] PMID: 23582322, PMCID: PMC3653129

15. Lovén J, Orlando DA, Sigova AA, Lin CY, Rahl PB, Burge CB, Levens DL, Lee TI,
Young RA. Revisiting global gene expression analysis. Cell. 2012; 151(3):476-82. 
NIHMSID: NIHMS416894 PubMed [journal] PMID: 23101621, PMCID: PMC3505597

16. Lin CY, Lovén J, Rahl PB, Paranal RM, Burge CB, Bradner JE, Lee TI, Young RA.
Transcriptional amplification in tumor cells with elevated c-Myc. Cell. 2012;
151(1):56-67. NIHMSID: NIHMS404733 PubMed [journal] PMID: 23021215, PMCID:
PMC3462372

17. White RM, Cech J, Ratanasirintrawoot S, Lin CY, Rahl PB, Burke CJ, Langdon E,
Tomlinson ML, Mosher J, Kaufman C, Chen F, Long HK, Kramer M, Datta S, Neuberg D,
Granter S, Young RA, Morrison S, Wheeler GN, Zon LI. DHODH modulates
transcriptional elongation in the neural crest and melanoma. Nature. 2011;
471(7339):518-22. NIHMSID: NIHMS333563 PubMed [journal] PMID: 21430780, PMCID:
PMC3759979

18. Rahl PB, Lin CY, Seila AC, Flynn RA, McCuine S, Burge CB, Sharp PA, Young RA.
c-Myc regulates transcriptional pause release. Cell. 2010; 141(3):432-45.
NIHMSID: NIHMS193332 PubMed [journal] PMID: 20434984, PMCID: PMC2864022

19. Orlando DA, Lin CY, Bernard A, Wang JY, Socolar JE, Iversen ES, Hartemink AJ,
Haase SB. Global control of cell-cycle transcription by coupled CDK and network
oscillators. Nature. 2008; 453(7197):944-7. NIHMSID: NIHMS140055 PubMed [journal]
PMID: 18463633, PMCID: PMC2736871

20. Orlando DA, Lin CY, Bernard A, Iversen ES, Hartemink AJ, Haase SB. A
probabilistic model for cell cycle distributions in synchrony experiments. Cell
cycle (Georgetown, Tex.). 2007; 6(4):478-88. PubMed [journal] PMID: 17329975

21. Wei X, Runnels JM, Lin CP. Selective uptake of indocyanine green by reticulocytes
in circulation. Investigative ophthalmology & visual science. 2003;
44(10):4489-96. NIHMSID: NIHMS161383 PubMed [journal] PMID: 14507897, PMCID:
PMC2830078