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GATA3-Controlled Nucleosome Eviction Drives MYC Enhancer Activity in T-Cell Development and Leukemia

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GATA3-Controlled Nucleosome Eviction Drives MYC Enhancer Activity in T-Cell Development and Leukemia Published OnlineFirst September 13, 2019; DOI: 10.1158/2159-8290.CD-19-0471 RESEARCH ARTICLE GATA3-Controlled Nucleosome Eviction Drives MYC Enhancer Activity in T-cell Development and Leukemia Laura Belver 1 , Alexander Y. Yang 1 , Robert Albero 1 , Daniel Herranz 2 , 3 , Francesco G. Brundu 4 , S. Aidan Quinn1 , Pablo Pérez-Durán 1 , Silvia Álvarez 1 , Francesca Gianni 1 , Marissa Rashkovan 1 , Devya Gurung1 , Pedro P. Rocha 5 , Ramya Raviram 6 , 7 , Clara Reglero 1 , Jose R. Cortés 1 , Anisha J. Cooke 1 , Agnieszka A. Wendorff1 , Valentina Cordó 8 , Jules P. Meijerink 8 , Raúl Rabadan 4 , 9 , and Adolfo A. Ferrando 1 , 4 , 10 , 11 ABSTRACT Long-range enhancers govern the temporal and spatial control of gene expres s ion; however, the mechanisms that regulate enhancer activity during normal and malig- nant development remain poorly understood. Here, we demonstrate a role for aberrant chromatin acces- sibility in the regulation of MYC expression in T-cell lymphoblastic leukemia (T-ALL). Central to this process, the NOTCH1-MYC enhancer (N-Me), a long-range T cell–specifi c MYC enhancer, shows dynamic changes in chromatin accessibility during T-cell specifi cation and maturation and an aberrant high degree of chromatin accessibility in mouse and human T-ALL cells. Mechanistically, we demonstrate that GATA3- driven nucleosome eviction dynamically modulates N-Me enhancer activity and is strictly required for NOTCH1-induced T-ALL initiation and maintenance. These results directly implicate aberrant regulation of chromatin accessibility at oncogenic enhancers as a mechanism of leukemic transformation. SIGNIFICANCE: MYC is a major effector of NOTCH1 oncogenic programs in T-ALL. Here, we show a major role for GATA3-mediated enhancer nucleosome eviction as a driver of MYC expression and leuke- mic transformation. These results support the role of aberrant chromatin accessibility and consequent oncogenic MYC enhancer activation in NOTCH1-induced T-ALL. 1 Institute for Cancer Genetics, Columbia University, New York, New Note: Supplementary data for this article are available at Cancer Discovery York. 2 Rutgers Cancer Institute of New Jersey, Rutgers University, New Online (http://cancerdiscovery.aacrjournals.org/). 3 Brunswick, New Jersey. Department of Pharmacology, Robert Wood A.Y. Yang and R. Albero contributed equally to this article. Johnson Medical School, Rutgers University, Piscataway, New Jersey. 4 Department of Systems Biology, Columbia University, New York, New Corresponding Author: Adolfo A. Ferrando, Institute for Cancer Genetics, York. 5 Division of Developmental Biology, Eunice Kennedy Shriver Columbia University Medical Center, 1130 St. Nicholas Avenue, ICRC- National Institute of Child Health and Human Development, NIH, Bethesda, 402A, New York, NY 10032. Phone: 212-851-4611; Fax: 212-851-5256; Maryland. 6 Ludwig Institute for Cancer Research, La Jolla, California. E-mail: [email protected] 7 Department of Chemistry and Biochemistry, University of California, San Cancer Discov 2019;9:1774–91 8 Diego, La Jolla, California. Department of Pediatric Oncology/Hematology, doi: 10.1158/2159-8290.CD-19-0471 Princess Maxima Center for Pediatric Oncology, Utrecht, the Nether- lands. 9 Department of Biomedical Informatics, Columbia University, New © 2019 American Association for Cancer Research. York, New York. 10 Department of Pediatrics, Columbia University Medical Center, New York, New York. 11 Department of Pathology, Columbia Univer- sity Medical Center, New York, New York. 1774 | CANCER DISCOVERY DECEMBER 2019 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst September 13, 2019; DOI: 10.1158/2159-8290.CD-19-0471 INTRODUCTION NOTCH1 and MYC share multiple common direct target genes driving leukemia cell growth in T-ALL (10). Consistently, the Enhancers are long-range, orientation-independent, cis- NOTCH1-MYC enhancer (N-Me), a NOTCH1-controlled acting DNA-regulatory elements that control gene expression T cell–specificMYC long-range enhancer, is strictly required for through physical interaction with proximal regulatory ele- NOTCH1-induced T-ALL (11). Notably, although activating ments located at gene promoters (1–3). Temporal and spatial mutations in NOTCH1 are also found in adenoid cystic carci- transcriptional regulation of key developmental factors is fre- noma (12, 13), chronic lymphocytic leukemia (14), and mantle quently coordinated by clusters of distal enhancers organized cell lymphomas (15), N-Me seems to be selectively active only in regulatory domains (4, 5). Active enhancers competent for during early T-cell development and in T-ALL (11). This obser- transcription factor binding and transcriptional regulation vation supports that yet unrecognized T cell–specific signaling, show low nucleosome occupancy (6, 7), and enhancers that transcriptional or epigenetic factors epistatic with NOTCH1 work simultaneously often display coordinated patterns of signaling are dominantly required for N-Me enhancer activity DNA accessibility, whereas those that work in mutually exclu- and may contribute to leukemic transformation. sive modes show divergent chromatin accessibility profiles (8). Constitutive activation of NOTCH1 signaling plays a promi- nent driver role in more than 60% of T-cell acute lympho- RESULTS blastic leukemias (T-ALL) harboring activating mutations in the NOTCH1 gene (9). Oncogenic NOTCH1 drives T-cell Dynamic Changes in Chromatin Accessibility transformation, activating a broad transcriptional program during Thymocyte Development that promotes leukemia cell growth and proliferation. Most T-cell precursors follow an orchestrated developmental prominently, NOTCH1 directly activates MYC expression, and program that begins with double negative 1 (DN1) cells, DECEMBER 2019 CANCER DISCOVERY | 1775 Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst September 13, 2019; DOI: 10.1158/2159-8290.CD-19-0471 RESEARCH ARTICLE Belver et al. A B Low High −3 0 3 DN1 DN1 DN2a DN2a DN2b DN2b DN3 DN3 DN4 DN4 ISP ISP DP DP CD4SP CD4SP CD8SP CD8SP DN1 Accessibility DN1 DN1 DN1 DN2a DN2a DN2b DN2b DN3 DN3 DN4 DN4 ISP ISP DP DP CD4SP CD4SP CD8SP CD8SP DN2a DN2a DN2b DN2b DN3 DN3 DN4 DN4 ISP ISP DP DP CD4SP CD4SP CD8SP CD8SP Consensus cluster value 0 0.5 1 C 1.5 1.5 1.5 1.5 1.0 1.0 1.0 1.0 0.5 0.5 0.5 0.5 0.0 0.0 Mean normalized signal Mean normalized signal Mean normalized signal 0.0 Mean normalized signal 0.0 DP DP DP DP DN1 DN3DN4 ISP DN1 DN3DN4 ISP DN1 DN3DN4 ISP DN1 DN3DN4 ISP DN2aDN2b DN2aDN2b DN2aDN2b DN2aDN2b CD4SPCD8SP CD4SPCD8SP CD4SPCD8SP CD4SPCD8SP DN1-DN2a DN2b-DN3 DN4-ISP-DP Mature CD4/CD8 SP Early T-cell precursors T-cell specification 100 100 100 100 75 75 75 75 50 50 50 50 Percentage 25 Percentage 25 Percentage 25 Percentage 25 0 0 0 0 x HOXHLH ETSFOX HOXHLHETSFOX HOXHLHETSFOX HOXHLHETSFOX GATARUNX KRAB GATARUNX KRAB GATARUNX KRAB GATA KRAB PU-box PU-box PU-box PU-bo RUNX Figure 1. Chromatin accessibility dynamics during T-cell development. A and B, Analysis of active genomic intervals in thymocyte populations. Unsupervised clustering heat map (A) and consensus clustering (k = 6; B) of the 10% most variable ATAC-seq peaks (n = 6,930) through the different T-cell precursor populations are shown. C, Chromatin accessibility profiles (top) and transcription factor binding site enrichment analysis (bottom) in active genomic intervals associated with the most relevant T-cell developmental stages. Bar graphs represent the percentage of active genomic intervals that contain a significant enrichment in transcription factor binding motifs for the PU-box, GATA, Runt-related (RUNX), homeodomain (HOX), helix-loop- helix (HLH), ETS, Forkhead-box (FOX), and Krüppel-like (KRAB) transcription factor families. the earliest cell entrants in the thymus, and progresses to 51.8%) and intergenic regions (26,947; 38.8%), and only a uncommitted DN2a progenitors, which become T-cell com- fraction reside in gene promoters (9,061; 13%). Interestingly, mitted as they mature into DN2b cells (16). These early pre- however, an increased representation of intergenic regions cursors subsequently progress through highly proliferative (3,194; 46%; P = 2–28) and decreased frequency of promoters DN3, DN4, and intermediate single positive (ISP) thymocyte (144; 2%; P = 4.8–148) is observed in ATAC-seq regions that stages, which then exit the cell cycle as they mature into display variable accessibility through T-cell development double positive (DP) and ultimately mature single positive stages, suggesting that dynamic control of accessibility at CD4+ (CD4SP) and CD8+ (CD8SP) T cells (16). Analysis of distal regulatory elements may influence thymocyte devel- chromatin accessibility by Assay for Transposase-Accessible opment. Hierarchical clustering analysis revealed distinct Chromatin using sequencing (ATAC-seq) in sorted mouse groups of differentially accessible regions that closely clus- thymocyte precursors identified 69,302 highly accessible tered thymocyte DN1 and DN2a populations, separate from regions. Most of these correspond to gene bodies (33,294; DN2b and DN3 cells, and DN4, ISP, and DP thymocytes 1776 | CANCER DISCOVERY DECEMBER 2019 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on October 2, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst September 13, 2019; DOI: 10.1158/2159-8290.CD-19-0471
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