Repression of p53-target gene Bbc3/PUMA by MYSM1 is essential for the survival of hematopoietic multipotent progenitors and contributes to stem cell maintenance

Cell Death and Differentiation
Jad I BelleAnastasia Nijnik

Abstract

p53 is a central mediator of cellular stress responses, and its precise regulation is essential for the normal progression of hematopoiesis. MYSM1 is an epigenetic regulator essential for the maintenance of hematopoietic stem cell (HSC) function, hematopoietic progenitor survival, and lymphocyte development. We recently demonstrated that all developmental and hematopoietic phenotypes of Mysm1 deficiency are p53-mediated and rescued in the Mysm1(-/-)p53(-/-) mouse model. However, the mechanisms triggering p53 activation in Mysm1(-/-) HSPCs, and the pathways downstream of p53 driving different aspects of the Mysm1(-/-) phenotype remain unknown. Here we show the transcriptional activation of p53 stress responses in Mysm1(-/-) HSPCs. Mechanistically, we find that the MYSM1 protein associates with p53 and colocalizes to promoters of classical p53-target genes Bbc3/PUMA (p53 upregulated modulator of apoptosis) and Cdkn1a/p21. Furthermore, it antagonizes their p53-driven expression by modulating local histone modifications (H3K27ac and H3K4me3) and p53 recruitment. Using double-knockout mouse models, we establish that PUMA, but not p21, is an important mediator of p53-driven Mysm1(-/-) hematopoietic dysfunction. Specifically, Mysm1(-/...Continue Reading

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Citations

Nov 12, 2016·Experimental Hematology·Jessica C Petrov, Anastasia Nijnik
Jan 10, 2017·Immunology·Michael FörsterAnastasia Nijnik
Jan 25, 2017·The Journal of Allergy and Clinical Immunology·Ehsan BahramiChristoph Klein
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Apr 30, 2020·International Journal of Molecular Sciences·Amanda FioreAnastasia Nijnik
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Feb 13, 2021·Cell Death and Differentiation·Margot E BowenLaura D Attardi
Nov 27, 2020·Advanced Science·Mingfu TianJianguo Wu
Apr 30, 2021·Frontiers in Immunology·Yun Hsiao LinAnastasia Nijnik

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Methods Mentioned

BETA
deubiquitination
immunoprecipitation
co-immunoprecipitations
acetylation
genotyping
FCS
FACS
electrophoresis
chip
RNA-Seq

Software Mentioned

MeV
featureCounts
FastQC
genomeCoverageBed
Bowtie
TopHat
Prism
wigToBigWig
edgeR Bioconductor
Trimmomatic

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