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Investigation of the Transcriptional Role of a RUNX1 Intronic Silencer by CRISPR/Cas9 Ribonucleoprotein in Acute Myeloid Leukemia Cells
Published on: September 1, 2019
The transcriptional corepressor MTG16a contains a novel nucleolar targeting sequence deranged in t (16; 21)-positive
André T Hoogeveen1, Stefano Rossetti, Violeta Stoyanova
1Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands. hoogeveen@ikg.fgg.eur.nl
Abstract:
The MTG (Myeloid Translocation Gene) proteins are a family of novel transcriptional corepressors. We report that MTG16a, a protein isoform encoded by the MTG16 gene deranged by the t (16; 21) in myeloid malignancies, is targeted to the nucleolus. The amino acid sequence necessary for nucleolar localization was mapped to the MTG16a N-terminal region. MTG16a, like MTG8, the nuclear corepressor deranged by the t (8; 21), is capable to interact with specific histone deacetylases (HDACs) suggesting that the protein may mediate silencing of nucleolar gene transcription. In addition, MTG16a is capable to form oligomers with other MTG proteins. As a consequence of the t (16; 21) the AML1 DNA-binding domain replaces the MTG16a N-terminal region. The AML1-MTG16 fusion protein is targeted to the nucleoplasm where it is capable to oligomerize with MTG16a and interact with HDAC1 and HDAC3. The deficiency of HDAC-containing complexes at nucleolar sites and the accumulation of HDAC-containing complexes at AML1-sites may be critical in the pathogenesis of t (16; 21) myeloid malignancies.
Insights
Myeloid Translocation Gene (MTG) proteins are novel corepressors. MTG16a
Area of Science:
- Molecular Biology
- Cancer Genetics
- Epigenetics
Background:
- Myeloid Translocation Gene (MTG) proteins function as transcriptional corepressors.
- The MTG16 gene is altered in myeloid malignancies by the t(16;21) translocation.
- MTG16a is a protein isoform encoded by the MTG16 gene.
Purpose of the Study:
- To investigate the function and localization of MTG16a.
- To elucidate the role of MTG16a in the pathogenesis of myeloid malignancies.
- To characterize the AML1-MTG16 fusion protein resulting from the t(16;21) translocation.
Main Methods:
- Amino acid sequence mapping to determine nucleolar localization.
- Interaction studies with histone deacetylases (HDACs).
- Oligomerization assays for MTG proteins and fusion proteins.
Main Results:
- MTG16a is localized to the nucleolus via its N-terminal region.
- MTG16a interacts with HDACs, suggesting a role in gene silencing.
- The AML1-MTG16 fusion protein localizes to the nucleoplasm and interacts with HDAC1 and HDAC3.
Conclusions:
- Alterations in MTG16a localization and function due to the t(16;21) translocation may contribute to myeloid malignancies.
- The interaction of the AML1-MTG16 fusion protein with HDACs and its altered localization are critical in disease pathogenesis.
- Deficiency of nucleolar HDACs and accumulation at AML1-binding sites are implicated in the development of t(16;21) myeloid malignancies.
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