ASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry.

Autor: Wang L; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore., Tan TK; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Durbin AD; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02216, USA.; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02215, USA.; The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Zimmerman MW; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02216, USA., Abraham BJ; Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38102, USA., Tan SH; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Ngoc PCT; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Weichert-Leahey N; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02216, USA.; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02215, USA., Akahane K; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02216, USA.; Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, 4093898, Japan., Lawton LN; Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA., Rokita JL; Oncology Division, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Department of Bioinformatics and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA., Maris JM; Oncology Division, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.; Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, 19104, USA., Young RA; Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA.; Biology Department, MIT, Cambridge, MA, 02142, USA., Look AT; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02216, USA. thomas_look@dfci.harvard.edu.; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA, 02215, USA. thomas_look@dfci.harvard.edu., Sanda T; Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. takaomi_sanda@nus.edu.sg.; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore. takaomi_sanda@nus.edu.sg.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2019 Dec 09; Vol. 10 (1), pp. 5622. Date of Electronic Publication: 2019 Dec 09.
DOI: 10.1038/s41467-019-13515-5
Abstrakt: A heritable polymorphism within regulatory sequences of the LMO1 gene is associated with its elevated expression and increased susceptibility to develop neuroblastoma, but the oncogenic pathways downstream of the LMO1 transcriptional co-regulatory protein are unknown. Our ChIP-seq and RNA-seq analyses reveal that a key gene directly regulated by LMO1 and MYCN is ASCL1, which encodes a basic helix-loop-helix transcription factor. Regulatory elements controlling ASCL1 expression are bound by LMO1, MYCN and the transcription factors GATA3, HAND2, PHOX2B, TBX2 and ISL1-all members of the adrenergic (ADRN) neuroblastoma core regulatory circuitry (CRC). ASCL1 is required for neuroblastoma cell growth and arrest of differentiation. ASCL1 and LMO1 directly regulate the expression of CRC genes, indicating that ASCL1 is a member and LMO1 is a coregulator of the ADRN neuroblastoma CRC.
Databáze: MEDLINE