The fusion of CLEC12A and MIR223HG arises from a trans‐splicing event in normal and transformed human cells

Dhungel, Bijay P., Monteuuis, Geoffray, Giardina, Caroline, Tabar, Mehdi S., Feng, Yue, Metierre, Cynthia, Ho, Sarah, Nagarajah, Rajini, Fontaine, Angela R.M., Shah, Jaynish S., Gokal, Divya, Bailey, Charles G., Schmitz, Ulf, and Rasko, John E.J. (2021) The fusion of CLEC12A and MIR223HG arises from a trans‐splicing event in normal and transformed human cells. International Journal of Molecular Sciences, 22. 12178.

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Abstract

Chimeric RNAs are often associated with chromosomal rearrangements in cancer. In addition, they are also widely detected in normal tissues, contributing to transcriptomic complexity. Despite their prevalence, little is known about the characteristics and functions of chimeric RNAs. Here, we examine the genetic structure and biological roles of CLEC12A‐MIR223HG, a novel chimeric transcript produced by the fusion of the cell surface receptor CLEC12A and the miRNA‐223 host gene (MIR223HG), first identified in chronic myeloid leukemia (CML) patients. Surprisingly, we observed that CLEC12A‐MIR223HG is not just expressed in CML, but also in a variety of normal tissues and cell lines. CLEC12A‐MIR223HG expression is elevated in pro‐monocytic cells resistant to chemotherapy and during monocyte‐to‐macrophage differentiation. We observed that CLEC12AMIR223HG is a product of trans‐splicing rather than a chromosomal rearrangement and that transcriptional activation of CLEC12A with the CRISPR/Cas9 Synergistic Activation Mediator (SAM) system increases CLEC12A‐MIR223HG expression. CLEC12A‐MIR223HG translates into a chimeric protein, which largely resembles CLEC12A but harbours an altered C‐type lectin domain altering key disulphide bonds. These alterations result in differences in post‐translational modifications, cellular localization, and protein–protein interactions. Taken together, our observations support a possible involvement of CLEC12A‐MIR223HG in the regulation of CLEC12A function. Our workflow also serves as a template to study other uncharacterized chimeric RNAs.

Item ID: 70820
Item Type: Article (Research - C1)
ISSN: 1422-0067
Keywords: chimeric RNAs; fusion RNAs encoding protein; fusion transcript; linc‐223; miR‐223 host gene; trans‐splicing; alternative splicing; CCL1; myeloid cell differentiation; C‐type lectin; chronic myeloid leukemia
Copyright Information: Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Funders: National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants: NHMRC 1177305, NHMRC 1196405
Date Deposited: 02 Dec 2021 00:23
FoR Codes: 31 BIOLOGICAL SCIENCES > 3102 Bioinformatics and computational biology > 310204 Genomics and transcriptomics @ 30%
31 BIOLOGICAL SCIENCES > 3101 Biochemistry and cell biology > 310102 Cell development, proliferation and death @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3211 Oncology and carcinogenesis > 321101 Cancer cell biology @ 20%
SEO Codes: 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280102 Expanding knowledge in the biological sciences @ 70%
28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280103 Expanding knowledge in the biomedical and clinical sciences @ 30%
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