PAF1 complex interactions with SETDB1 mediate promoter H3K9 methylation and transcriptional repression of Hoxa9 and Meis1 in acute myeloid leukemia

Oncotarget
J RopaAndrew G Muntean

Abstract

The Polymerase Associated Factor 1 complex (PAF1c) is an epigenetic co-modifying complex that directly contacts RNA polymerase II (RNAPII) and several epigenetic regulating proteins. Mutations, overexpression and loss of expression of subunits of the PAF1c are observed in various forms of cancer suggesting proper regulation is needed for cellular development. However, the biochemical interactions with the PAF1c that allow dynamic gene regulation are unclear. We and others have shown that the PAF1c makes a direct interaction with MLL fusion proteins, which are potent oncogenic drivers of acute myeloid leukemia (AML). This interaction is critical for the maintenance of MLL translocation driven AML by targeting MLL fusion proteins to the target genes Meis1 and Hoxa9. Here, we use a proteomics approach to identify protein-protein interactions with the PAF1c subunit CDC73 that regulate the function of the PAF1c. We identified a novel interaction with a histone H3 lysine 9 (H3K9) methyltransferase protein, SETDB1. This interaction is stabilized with a mutant CDC73 that is incapable of supporting AML cell growth. Importantly, transcription of Meis1 and Hoxa9 is reduced and promoter H3K9 trimethylation (H3K9me3) increased by overexpres...Continue Reading

References

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Citations

Dec 30, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Nirmalya Saha, Andrew G Muntean
May 6, 2021·International Journal of Laboratory Hematology·Maria Stella De CandiaDomenico Pastore
Aug 28, 2021·Life·Mariam MarkouliChristina Piperi

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Methods Mentioned

BETA
monubiquitination
transfection
immunoprecipitation
Affinity Purification
RNA-seq
transfections
ChIP
Fusion Tribrid
PCR

Software Mentioned

- HT Proteome Discoverer
R
GeneMANIA
SAS
Percolator
SEQUEST
CRAPome
Significance Analysis of Interactome ( SAINT )
cBioPortal
SAINT

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