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HOTTIP-dependent R-loop formation regulates CTCF boundary activity and TAD integrity in leukemia.
Luo, Huacheng; Zhu, Ganqian; Eshelman, Melanie A; Fung, Tsz Kan; Lai, Qian; Wang, Fei; Zeisig, Bernd B; Lesperance, Julia; Ma, Xiaoyan; Chen, Shi; Cesari, Nicholas; Cogle, Christopher; Chen, Baoan; Xu, Bing; Yang, Feng-Chun; So, Chi Wai Eric; Qiu, Yi; Xu, Mingjiang; Huang, Suming.
Afiliación
  • Luo H; Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
  • Zhu G; Department of Molecular Medicine, the University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3904, USA.
  • Eshelman MA; Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
  • Fung TK; School of Cancer and Pharmaceutical Science, King's College London, London SE5 9NU, UK; Department of Haematological Medicine, King's College Hospital, London SE5 9RS, UK.
  • Lai Q; Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
  • Wang F; Department of Hematology and Oncology, The Affiliated Zhongda Hospital, Southeast University Medical School, Nanjing 21009, China.
  • Zeisig BB; School of Cancer and Pharmaceutical Science, King's College London, London SE5 9NU, UK; Department of Haematological Medicine, King's College Hospital, London SE5 9RS, UK.
  • Lesperance J; Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
  • Ma X; Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Department of Hematology and Oncology, The Affiliated Zhongda Hospital, Southeast University Medical School, Nanjing 21009, China.
  • Chen S; Department of Molecular Medicine, the University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3904, USA.
  • Cesari N; Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
  • Cogle C; Division of Hematology/Oncology, Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
  • Chen B; Department of Hematology and Oncology, The Affiliated Zhongda Hospital, Southeast University Medical School, Nanjing 21009, China.
  • Xu B; Department of Hematology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China.
  • Yang FC; Department of Cell System & Anatomy, the University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3904, USA; Mays Cancer Center, Joe R. & Teresa Lozano Long School of Medicine, the University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3904, US
  • So CWE; School of Cancer and Pharmaceutical Science, King's College London, London SE5 9NU, UK; Department of Haematological Medicine, King's College Hospital, London SE5 9RS, UK. Electronic address: eric.so@kcl.ac.uk.
  • Qiu Y; Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. Electronic address: yqiu1@pennstatehealth.psu.edu.
  • Xu M; Department of Molecular Medicine, the University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3904, USA; Department of Cell System & Anatomy, the University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3904, USA. Electronic address: xum1@uthscsa.ed
  • Huang S; Division of Pediatric Hematology/Oncology, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Penn State Cancer Institute, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. Electronic address: shuang4@pennstatehealth.psu.edu.
Mol Cell ; 82(4): 833-851.e11, 2022 02 17.
Article en En | MEDLINE | ID: mdl-35180428
HOTTIP lncRNA is highly expressed in acute myeloid leukemia (AML) driven by MLL rearrangements or NPM1 mutations to mediate HOXA topologically associated domain (TAD) formation and drive aberrant transcription. However, the mechanism through which HOTTIP accesses CCCTC-binding factor (CTCF) chromatin boundaries and regulates CTCF-mediated genome topology remains unknown. Here, we show that HOTTIP directly interacts with and regulates a fraction of CTCF-binding sites (CBSs) in the AML genome by recruiting CTCF/cohesin complex and R-loop-associated regulators to form R-loops. HOTTIP-mediated R-loops reinforce the CTCF boundary and facilitate formation of TADs to drive gene transcription. Either deleting CBS or targeting RNase H to eliminate R-loops in the boundary CBS of ß-catenin TAD impaired CTCF boundary activity, inhibited promoter/enhancer interactions, reduced ß-catenin target expression, and mitigated leukemogenesis in xenograft mouse models with aberrant HOTTIP expression. Thus, HOTTIP-mediated R-loop formation directly reinforces CTCF chromatin boundary activity and TAD integrity to drive oncogene transcription and leukemia development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cromatina / Leucemia Mieloide Aguda / Beta Catenina / ARN Largo no Codificante / Factor de Unión a CCCTC / Estructuras R-Loop Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Cromatina / Leucemia Mieloide Aguda / Beta Catenina / ARN Largo no Codificante / Factor de Unión a CCCTC / Estructuras R-Loop Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos