Nuclear export of chimeric mRNAs depends on an lncRNA-triggered autoregulatory loop

Chen, Z.-H.; Zen, Z.; Chen, T.-Q.; Han, C.; Sun, Y.-M.; Huang, W.; Sun, L.-Y.; Fang, K.; Luo, X.-Q.; Wang, W.-T.; Chen, M. Y.

doi:10.1101/426742

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bioRxiv · 10.1101/426742

Nuclear export of chimeric mRNAs depends on an lncRNA-triggered autoregulatory loop

Chen, Z.-H.·Zen, Z.·Chen, T.-Q.·Han, C.·Sun, Y.-M.·Huang, W.·Sun, L.-Y.·Fang, K.·Luo, X.-Q.·Wang, W.-T.·Chen, M. Y.

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Abstract

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.

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Chen, Z.-H., Zen, Z., Chen, T.-Q., Han, C., Sun, Y.-M., Huang, W., Sun, L.-Y., Fang, K., Luo, X.-Q., Wang, W.-T., Chen, M. Y.. 2018-09-25. Nuclear export of chimeric mRNAs depends on an lncRNA-triggered autoregulatory loop. https://doi.org/10.1101/426742

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