CBFβ-SMMHC Affects Genome-wide Polycomb Repressive Complex 1 Activity in Acute Myeloid Leukemia
Gaëlle Cordonnier1, Amit Mandoli2, Nicolas Cagnard3
1Université Paris Descartes Sorbonne Cité, Institut Necker Enfants Malades (INEM), Institut National de Recherche Médicale (INSERM) U1151, Paris, France; Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker-Enfants Malades, Paris, France.
Abstract:
Mutations and deletions of polycomb repressive complex (PRC) components are increasingly recognized to affect tumor biology in a range of cancers. However, little is known about how genetic alterations of PRC-interacting molecules such as the core binding factor (CBF) complex influence polycomb activity. We report that the acute myeloid leukemia (AML)-associated CBFβ-SMMHC fusion oncoprotein physically interacts with the PRC1 complex and that these factors co-localize across the AML genome in an apparently PRC2-independent manner. Depletion of CBFβ-SMMHC caused substantial increases in genome-wide PRC1 binding and marked changes in the association between PRC1 and the CBF DNA-binding subunit RUNX1. PRC1 was more likely to be associated with actively transcribed genes in CBFβ-SMMHC-expressing cells. CBFβ-SMMHC depletion had heterogeneous effects on gene expression, including significant reductions in transcription of ribosomal loci occupied by PRC1. Our results provide evidence that CBFβ-SMMHC markedly and diversely affects polycomb recruitment and transcriptional regulation across the AML genome.
Insights
The CBFβ-SMMHC oncoprotein interacts with the Polycomb Repressive Complex 1 (PRC1) in acute myeloid leukemia (AML). This interaction alters PRC1 binding and gene expression across the AML genome.
Area of Science:
- Molecular Biology
- Cancer Genetics
- Epigenetics
Background:
- Mutations in Polycomb Repressive Complex (PRC) components impact tumor biology.
- The influence of PRC-interacting molecules, like the core binding factor (CBF) complex, on polycomb activity remains largely unknown.
Purpose of the Study:
- To investigate the interaction between the acute myeloid leukemia (AML)-associated CBFβ-SMMHC fusion oncoprotein and the PRC1 complex.
- To understand how CBFβ-SMMHC affects polycomb activity and gene regulation in AML.
Main Methods:
- Investigated the physical interaction and co-localization of CBFβ-SMMHC with PRC1 in AML cells.
- Utilized depletion of CBFβ-SMMHC to assess changes in genome-wide PRC1 binding and its association with RUNX1.
- Analyzed gene expression changes, particularly focusing on ribosomal loci.
Main Results:
- CBFβ-SMMHC physically interacts with and co-localizes with PRC1 across the AML genome, independent of PRC2.
- Depletion of CBFβ-SMMHC led to increased genome-wide PRC1 binding and altered PRC1-RUNX1 association.
- PRC1 preferentially associated with actively transcribed genes in CBFβ-SMMHC-expressing cells, and its depletion reduced ribosomal gene transcription.
Conclusions:
- CBFβ-SMMHC significantly impacts polycomb recruitment and transcriptional regulation in AML.
- The findings elucidate a novel mechanism by which a fusion oncoprotein influences epigenetic regulation in cancer.
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