期刊
NUCLEIC ACIDS RESEARCH
卷 46, 期 12, 页码 6041-6056出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky366
关键词
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资金
- National Natural Science Foundation of China [31470757, 81772875]
- ShuGuang Project of Shanghai Municipal Education Commission [17SG19]
- Shanghai Education Development Foundation [17SG19]
- Outstanding Yong Medical Scholar of Shanghai Municipal Commission of Health and Family Planning [2017YQ067]
- Program for Professor of Special Appointment (Eastern Scholar) at the Shanghai Institutions of Higher Learning [1410000159]
- SMC-ChenXing Yong Scholar Program
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant [20161317]
- Outstanding Yong Scholar Grant of Shanghai Jiao Tong University School of Medicine [16XJ11002]
Aberrant chromatin transformation dysregulates gene expression and may be an important driver of tumorigenesis. However, the functional role of chromosomal dynamics in tumorigenesis remains to be elucidated. Here, using in vitro and in vivo experiments, we reveal a novel long noncoding (lncing) driver at chr12p13.3, in which a novel lncRNA (G) under bar ALNT8 (A) under bar ntisense (U) under bar pstream (1) under bar (GAU1) is initially activated by an open chromatin status, triggering recruitment of the transcription elongation factor TCEA1 at the oncogene GALNT8 promoter and cis-activates the expression of GALNT8. Analysis of The Cancer Genome Atlas (TCGA) clinical database revealed that the GAU1/GALNT8 driver serves as an important indicative biomarker, and targeted silencing of GAU1 via the HKP-encapsulated method exhibited therapeutic efficacy in orthotopic xenografts. Our study presents a novel oncogenetic mechanism in which aberrant tuning of the chromatin state at specific chromosomal loci exposes factor-binding sites, leading to recruitment of trans-factor and activation of oncogenetic driver, thereby provide a novel alternative concept of chromatin dynamics in tumorigenesis.
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