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

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 noncoding 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.

The role of M6A modification in the regulation of tumor-related lncRNAs

“…134 MALAT1 could also regulate the output of chimeric mRNA in an m 6 A-dependent manner, including YTHDC1 and METTL14, thereby controlling the differentiation of hematopoietic cells. 135 Wang et al 136 further revealed that YTHDC1 recognition of MALAT1-m 6 A plays a key role in maintaining the composition of nuclear spots and genomic binding sites, thereby regulating the expression of several key oncogenes, and artificial tethering of YTHDC1 to m 6 A-deficient MALAT1 largely saved the metastatic potential of cancer cells. The Hox transcript antisense intergenic RNA (HOTAIR) is a lncRNA of about 2.2 kb that is transcribed from the antisense strand of the developmental the HOXC gene cluster on chromosome 12, and Meyer et al 137 used methylated RNA immunoprecipitation followed by sequencing (MeRIP-seq) in HEK293T cells and found a single m 6 A peak region (126nt) in the front half of HOTAIR, which did not overlap with m 5 C. Dominissini et al 138 mapped m 6 A to the lncRNAs, for instance, PVT1 and NEAT1 and uncharacterized lncRNA transcripts.…”

Long Non-Coding RNA-Ribonucleoprotein Networks in the Post-Transcriptional Control of Gene Expression

“…Chimeric mRNAs resulting from genomic rearrangements need to be translocated to the cytoplasm in order to be translated into the resulting oncogenic proteins [35]. Wang and coworkers recently reported on the involvement of the MALAT1 in the regulation of nuclear export of chimeric mRNAs encoding the oncogenic fusion proteins PML-RARA, MLL-AF9, MLL-ENL, and AML1-ETO [36]. These authors show that nuclear export of the chimeric mRNAs depends on the MALAT1 expression levels [36].…”

“…Wang and coworkers recently reported on the involvement of the MALAT1 in the regulation of nuclear export of chimeric mRNAs encoding the oncogenic fusion proteins PML-RARA, MLL-AF9, MLL-ENL, and AML1-ETO [36]. These authors show that nuclear export of the chimeric mRNAs depends on the MALAT1 expression levels [36]. They propose a complex regulatory mechanism that involves the methylation of mRNAs to form N6-methyladenosine (m6A).…”

“…m6A has been reported to enhance mRNA export from the nucleus through the interaction of the m6A-modified mRNAs with the "reader" RBPs YTHDC1 and SRSF3 that function as adaptors for the NXF1-dependent mRNA export pathway [37]. Wang and coworkers provide evidence that MALAT1, upon interaction with oncogenic fusion proteins in nuclear speckles, promotes the interaction between the fusion proteins and the m6A methyltransferase cofactor METTL14 thus controlling the chimeric mRNA-exporting process through the m6A reader YTHDC1 [36]. The results of this study suggest the possibility that other lncRNAs, besides MALAT1, could provide a platform for the association of m6A "readers" with m6A-modified specific mRNAs to influence their nuclear export.…”

The m6A writers regulated by the IL-6/STAT3 inflammatory pathway facilitate cancer cell stemness in cholangiocarcinoma

“…N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotic cells 11,12 . Accumulated evidence has indicated that m6A plays critical roles in multiple biological processes, and aberrant m6A modification is closely associated with cancers [12][13][14][15][16] . The breakthrough in the discovery and understanding of m6A writers, erasers, and readers, together with the development of high-throughput assays, have helped to elucidate the biological functions and the underlying mechanisms of m6A 12,17,18 .…”