HNRNPK is retained in the cytoplasm by Keratin 19 to stabilize target mRNAs

Heterogeneous nuclear ribonucleoprotein K (HNRNPK) regulates pre-mRNA processing and long non-coding RNA localization in the nucleus. It was previously shown that shuttling of HNRNPK to the cytoplasm promotes cell proliferation and cancer metastasis. However, the mechanism of HNRNPK cytoplasmic localization, its cytoplasmic RNA ligands, and impact on posttranscriptional gene regulation remain uncharacterized. Here we show that the intermediate filament protein Keratin 19 (K19) directly interacts with HNRNPK and sequesters it in the cytoplasm. Correspondingly, in K19 knockout breast cancer cells, HNRNPK does not localize in the cytoplasm, resulting in reduced cell proliferation. We mapped cytoplasmic HNRNPK target mRNAs using PAR-CLIP where transcriptome data to show that, in the cytoplasm, HNRNPK stabilizes target mRNAs bound to the 3’ untranslated region at the expected C-rich sequence elements. Furthermore, these mRNAs are typically involved in cancer progression and include the p53 signaling pathway that is dysregulated upon HNRNPK knockdown or K19 knockout. This study identifies how a cytoskeletal protein can directly regulate gene expression by controlling subcellular localization of RNA binding proteins to support pathways involved in cancer progression

Genome-wide efficient attribute selection for purely epistatic models via Shannon entropy

Epistasis plays an important role in the genetic architecture of common human diseases. Most complex diseases are believed to have multiple contributing loci that often have subtle patterns which make them fairly difficult to find in large data sets. Disorders that follow purely epistatic models cannot be detected by cases/control studies based on individual analysis of susceptible loci. The computational complexity of performing exhaustive searches for detecting such models in genome-wide applications is practically unfeasible. Furthermore, with ever-increasing number of both genotypes and individuals on one side, and little knowledge of complex traits on the other, it is becoming fairly difficult and time consuming to perform systematic genome-wide studies on such traits. We present and discuss a convenient framework for modelling epistasis using information theoretic concepts and algorithms inspired by such an approach. These generalised algorithms, which are especially in favour of purely epistatic models, are applied to both simulated and real data. The real data represents the genotype-phenotype values for Age-Related Macular Degeneration (AMD) disease. Many two-locus purely epistatic patterns were found for AMD. A new visualisation approach is also presented for the purpose of better illustrating epistasy for cases where the number of loci is more than two or three

Keratin 19 binds and regulates cytoplasmic HNRNPK mRNA targets in triple-negative breast cancer

Abstract Background Heterogeneous nuclear ribonucleoprotein K (HNRNPK) regulates pre-mRNA processing and long non-coding RNA localization in the nucleus. It was previously shown that shuttling of HNRNPK to the cytoplasm promotes cell proliferation and cancer metastasis. However, the mechanism of HNRNPK cytoplasmic localization, its cytoplasmic RNA ligands, and impact on post-transcriptional gene regulation remain uncharacterized. Results Here we show that the intermediate filament protein Keratin 19 (K19) directly interacts with HNRNPK and sequesters it in the cytoplasm. Correspondingly, in K19 knockout breast cancer cells, HNRNPK does not localize in the cytoplasm, resulting in reduced cell proliferation. We comprehensively mapped HNRNPK binding sites on mRNAs and showed that, in the cytoplasm, K19-mediated HNRNPK-retention increases the abundance of target mRNAs bound to the 3’ untranslated region (3’UTR) at the expected cytidine-rich (C-rich) sequence elements. Furthermore, these mRNAs protected by HNRNPK in the cytoplasm are typically involved in cancer progression and include the p53 signaling pathway that is dysregulated upon HNRNPK knockdown (HNRNPK KD) or K19 knockout (KRT19 KO). Conclusions This study identifies how a cytoskeletal protein can directly regulate gene expression by controlling the subcellular localization of RNA-binding proteins to support pathways involved in cancer progression

Additional file 6 of Keratin 19 binds and regulates cytoplasmic HNRNPK mRNA targets in triple-negative breast cancer

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Additional file 9 of Keratin 19 binds and regulates cytoplasmic HNRNPK mRNA targets in triple-negative breast cancer

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Additional file 5 of Keratin 19 binds and regulates cytoplasmic HNRNPK mRNA targets in triple-negative breast cancer

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Additional file 1 of Keratin 19 binds and regulates cytoplasmic HNRNPK mRNA targets in triple-negative breast cancer

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Additional file 2 of Keratin 19 binds and regulates cytoplasmic HNRNPK mRNA targets in triple-negative breast cancer

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