Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia

Abstract

DNA mutations are known cancer drivers. Here we investigated whether mRNA events that are upregulated in cancer can functionally mimic the outcome of genetic alterations. RNA sequencing or 3'-end sequencing techniques were applied to normal and malignant B cells from 59 patients with chronic lymphocytic leukaemia (CLL). We discovered widespread upregulation of truncated mRNAs and proteins in primary CLL cells that were not generated by genetic alterations but instead occurred by intronic polyadenylation. Truncated mRNAs caused by intronic polyadenylation were recurrent (n = 330) and predominantly affected genes with tumour-suppressive functions. The truncated proteins generated by intronic polyadenylation often lack the tumour-suppressive functions of the corresponding full-length proteins (such as DICER and FOXN3), and several even acted in an oncogenic manner (such as CARD11, MGA and CHST11). In CLL, the inactivation of tumour-suppressor genes by aberrant mRNA processing is substantially more prevalent than the functional loss of such genes through genetic events. We further identified new candidate tumour-suppressor genes that are inactivated by intronic polyadenylation in leukaemia and by truncating DNA mutations in solid tumours. These genes are understudied in cancer, as their overall mutation rates are lower than those of well-known tumour-suppressor genes. Our findings show the need to go beyond genomic analyses in cancer diagnostics, as mRNA events that are silent at the DNA level are widespread contributors to cancer pathogenesis through the inactivation of tumour-suppressor genes.

FOXN3 controls liver glucose metabolism by regulating gluconeogenic substrate selection

“…These results mirror the effects seen in zebrafish mutants carrying a heterozygous foxn3 loss-of-function allele where a 50% reduction in foxn3 transcript was accompanied by a twofold increase in mycb transcript (Karanth et al, 2018). These effects are also similar to that observed when immortalized human cells are transduced with a dominant-negative FOXN3 cDNA that occurs in leukemia as a consequence of pathological intron polyadenylation (Lee et al, 2018). Knock-down of Foxn3 in mouse livers decreased fasting blood glucose (Fig.…”

In vivomeasurements reveal a single 5’ intron is sufficient to increase protein expression level inC. elegans

“…Many previous reports have shown that introns influence human diseases. These diseases fall into two broad classes: heritable diseases (RILEY AND KRIEGER 2005;SWARBRICK et al 2011;VAZ-DRAGO et al 2017) and cancers (HSU et al 2015;JUNG et al 2015;WIESNER et al 2015;NERI et al 2017;LEE et al 2018). The intron-dependent processes that are affected often unknown, poorly understood, or if understood, lack experimental means to determine how to suppress the intron-related pathology.…”

Streamlined low-input transcriptomics through EASY-RNAseq

“…At the same time, a large proportion of data mapped to non-coding region was noticed, including both intronic and intergenic regions. These reads suggest that there may be complex post-transcriptional regulation mechanisms occurring in the cells that has been previously underappreciated, but which EASY RNAseq may be able to successfully detect (11)(12)(13)(14).…”