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Identification of chimeric TSNAX-DISC1 resulting from intergenic splicing in endometrial carcinoma through
Na Li1, Jian Zheng1, Hua Li2
1Department of Genetics, Medical College of Soochow University, Suzhou 215123, China, Department of Obstetrics and Gynecology, Third Hospital, Peking University, Beijing 100191, China, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, San Xiang Road No. 1055, Suzhou 215004, China, Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94304, USA and The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory Disease, Guangzhou Medical University, Guangzhou 510182, China.
Abstract:
Gene fusion is among the primary processes that generate new genes and has been well characterized as potent pathway of oncogenesis. Here, by high-throughput RNA sequencing in nine paired human endometrial carcinoma (EC) and matched non-cancerous tissues, we obtained that chimeric translin-associated factor X-disrupted-in-schizophrenia 1 (TSNAX-DISC1) occurred significantly upregulated in multiple EC samples. Experimental investigation showed that TSNAX-DISC1 appears to be formed by splicing without chromosomal rearrangement. The chimera expression inversely correlated with the binding of CCCTC-binding factor (CTCF) to the insulators. Subsequent investigations indicate that long intergenic non-coding RNA lincRNA-NR_034037, separating TSNAX from DISC1, regulates TSNAX -DISC1 production and TSNAX/DISC1 expression levels by extricating CTCF from insulators. Dysregulation of TSNAX influences steroidogenic factor-1-stimulated transcription on the StAR promoter, altering progesterone actions, implying the association with cancer. Together, these results advance our understanding of the mechanism in which lincRNA-NR_034037 regulates TSNAX-DISC1 formation programs that tightly regulate EC development.
Insights
A novel gene fusion, TSNAX-DISC1, is upregulated in endometrial carcinoma (EC). A long non-coding RNA, lincRNA-NR_034037, regulates its formation, impacting EC development.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- Gene fusions are key drivers of oncogenesis.
- Endometrial carcinoma (EC) development involves complex genetic alterations.
Purpose of the Study:
- To investigate novel gene fusions in human endometrial carcinoma.
- To elucidate the regulatory mechanisms of oncogenic gene fusions in EC.
Main Methods:
- High-throughput RNA sequencing of paired EC and non-cancerous tissues.
- Experimental validation of gene fusion formation and regulation.
- Analysis of CCCTC-binding factor (CTCF) and lincRNA interactions.
Main Results:
- A novel chimeric gene, translin-associated factor X-disrupted-in-schizophrenia 1 (TSNAX-DISC1), was significantly upregulated in EC.
- TSNAX-DISC1 formation occurs via splicing, not chromosomal rearrangement.
- lincRNA-NR_034037 regulates TSNAX-DISC1 production by modulating CTCF binding to insulators.
- TSNAX dysregulation impacts steroidogenic factor-1 transcription and progesterone action, linking it to EC.
Conclusions:
- lincRNA-NR_034037 plays a critical role in regulating TSNAX-DISC1 formation in EC.
- The TSNAX-DISC1 fusion and its regulatory pathway represent a potential target for EC therapies.
- Understanding these novel mechanisms advances knowledge of EC pathogenesis.
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