Page 123 - Haematologica May 2022

Non-Hodgkin Lymphoma
Characterization of GECPAR, a noncoding RNA that regulates the transcriptional pro- gram of diffuse large B-cell lymphoma
Sara Napoli,1 Luciano Cascione,1,2 Andrea Rinaldi,1 Filippo Spriano,1 Francesca Guidetti,1 Fangwen Zhang,1 Maria Teresa Cacciapuoti,3 Afua Adjeiwaa Mensah,1 Giulio Sartori,1 Nicolas Munz,1 Mattia Forcato,4 Silvio Bicciato4, Annalisa Chiappella,5 Paola Ghione,6 Olivier Elemento,7,8 Leandro Cerchietti, 6Giorgio Inghirami3 and Francesco Bertoni1,9
1Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland; 2SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland; 3Pathology and Laboratory Medicine Department, Weill Cornell Medicine, New York, NY, USA; 4Center for Genome Research, Department of Life Sciences University of Modena and Reggio, Modena, Italy; 5Ematologia, A.O.U. Città della Salute e della Scienza di Torino, Turin, Italy; 6Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, USA; 7Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA; 8Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA and 9Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
ABSTRACT
Enhancers are regulatory regions of DNA, which play a key role in cell-type specific differentiation and development. Most active enhancers are transcribed into enhancer RNA (eRNA) that can reg- ulate transcription of target genes by means of in cis as well as in trans action. eRNA stabilize contacts between distal genomic regions and mediate the interaction of DNA with master transcription factors. Here, we characterized an enhancer eRNA, GECPAR (germinal center prolifer- ative adapter RNA), which is specifically transcribed in normal and neo- plastic germinal center B cells from the super-enhancer of POU2AF1, a key regulatory gene of the germinal center reaction. Using diffuse large B-cell lymphoma cell line models, we demonstrated the tumor suppres- sor activity of GECPAR, which is mediated via its transcriptional regula- tion of proliferation and differentiation genes, particularly MYC and the Wnt pathway.
Introduction
Enhancers are regulatory DNA regions that positively drive gene transcription across neighboring genomic regions spanning many megabases and are character- ized by distinct epigenetic features:1,2 a high ratio of H3K4me1 to H3K4me3; enrichment of H3K27ac, which is deposited by the CREBBP/p300 complex;3 high accessibility to chromatin readers such as bromodomain and extraterminal domain (BET) proteins and transcription factors (TF). Some enhancers are actively transcribed giving rise to noncoding RNA called enhancer RNA (eRNA).4 Transcribed enhancers are more acetylated, more enriched of TF and co-activa- tors, and are also more active in the transactivation of promoters, with which they interact inside 3D structures called enhancer-promoter loops.5 Clusters of enhancers, called super-enhancers (SE), are strongly transcribed and produce sev- eral eRNA controlling key genes, which regulate cellular development and differ- entiation.6,7 eRNA are crucial components of the regulatory chromatin machinery that controls the expression of key context-specific, protein-coding genes. They usually stabilize multiprotein complexes and constitute a scaffold for DNA loops by enforcing interactions between distant DNA regions, including those located on different chromosomes.8-11 As they lack a poly A tail, their activity is restrained to the site of transcription and they undergo rapid decay. However, polyadenylat- ed long intergenic non-coding RNA (lincRNA) also comprise enhancer-derived
Ferrata Storti Foundation
Haematologica 2022 Volume 107(5):1131-1143
Correspondence:
FRANCESCO BERTONI
francesco.bertoni@ior.usi.ch
SARA NAPOLI
sara.napoli@ior.usi.ch
https://doi.org/10.3324/haematol.2020.267096 ©2022 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
haematologica | 2022; 107(5)
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ARTICLE
Received: July 29, 2020. Accepted: June 16, 2021. Pre-published: June 24, 2021.