PT  - JOURNAL ARTICLE
AU  - Zhen-Hua Chen
AU  - Zhan-Cheng Zeng
AU  - Tian-Qi Chen
AU  - Cai Han
AU  - Yu-Meng Sun
AU  - Wei Huang
AU  - Lin-Yu Sun
AU  - Ke Fang
AU  - Xue-Qun Luo
AU  - Wen-Tao Wang
AU  - Yue-Qin Chen
TI  - Nuclear export of chimeric mRNAs depends on an lncRNA-triggered autoregulatory loop
AID  - 10.1101/426742
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 426742
4099  - http://biorxiv.org/content/early/2018/09/25/426742.short
4100  - http://biorxiv.org/content/early/2018/09/25/426742.full
AB  - Aberrant chromosomal translocations leading to tumorigenesis have been ascribed to the heterogeneously oncogenic functions. However, how fusion transcripts exporting remains to be declared. Here, we showed that the nuclear speckle-specific long non coding RNA MALAT1 controls chimeric mRNA export processes and regulates myeloid progenitor cell differentiation in malignant hematopoiesis. We demonstrated that MALAT1 regulates chimeric mRNAs export in an m6A-dependent manner and thus controls hematopoietic cell differentiation. Specifically, reducing MALAT1 or m6A methyltransferases and the ‘reader’ YTHDC1 result in the universal retention of distinct oncogenic gene mRNAs in nucleus. Mechanically, MALAT1 hijacks both the chimeric mRNAs and fusion proteins in nuclear speckles during chromosomal translocations and mediates the colocalization of oncogenic fusion proteins with METTL14. MALAT1 and fusion protein complexes serve as a functional loading bridge for the interaction of chimeric mRNA and METTL14. This study demonstrated a universal mechanism of chimeric mRNA transport that involves lncRNA-fusion protein-m6A autoregulatory loop for controlling myeloid cell differentiation. Targeting the lncRNA-triggered autoregulatory loop to disrupt chimeric mRNA transport might represent a new common paradigm for treating blood malignancies.