Repression of p53-target gene Bbc3/puma by MYSM1 is essential for the survival of hematopoietic multipotent progenitors and contributes to stem cell maintenance
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ABSTRACT:
PROVIDER: PRJNA633124 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11798129_1.fastq.gz | Fastqsanger.gz | |||
| SRR11798129_2.fastq.gz | Fastqsanger.gz | |||
| SRR11798130_1.fastq.gz | Fastqsanger.gz | |||
| SRR11798130_2.fastq.gz | Fastqsanger.gz | |||
| SRR11798131_1.fastq.gz | Fastqsanger.gz |
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Project description:MYSM1 is a transcriptional regulator essential for HSC function and hematopoiesis. We established that p53 activation is a common mechanism mediating HSC dysfunction, MPP depletion, and lymphopenia in Mysm1-deficiency, however, the specific p53-induced effectors that trigger dysfunction in Mysm1-deficient HSPCs remain unknown. Here, we performed RNA-Seq of Lin-cKit+Sca1+CD150+ and CD150- HSPCs from Mysm1-/-Puma-/-, Mysm1-/-Puma+/-, Puma-/-, and wild-type mice; (Mysm1-/-Puma+/- phenocopies Mysm1-/-). We showed that Bbc3/PUMA is the primary non-redundant mediator of MPP depletion in Mysm1-deficiency and contributes to HSC dysfunction, whereas depletion of lymphoid-lineage cells involves PUMA-independent p53 activities. We also identified a broad downregulation of genes encoding protein components of the ribosome (RP-genes) and other regulators of translation in Mysm1-deficiency, and the downregulation persisted in Mysm1-/-Puma-/-.
2020-07-22 | GSE150665 | GEO
Project description: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(-/-)Puma(-/-) mice show full rescue of multipotent progenitor (MPP) viability, partial rescue of HSC quiescence and function, but persistent lymphopenia. Through transcriptome analysis of Mysm1(-/-)Puma(-/-) MPPs, we demonstrate strong upregulation of other p53-induced mediators of apoptosis and cell-cycle arrest. The full viability of Mysm1(-/-)Puma(-/-) MPPs, despite strong upregulation of many other pro-apoptotic mediators, establishes PUMA as the essential non-redundant effector of p53-induced MPP apoptosis. Furthermore, we identify potential mediators of p53-dependent but PUMA-independent Mysm1(-/-)hematopoietic deficiency phenotypes. Overall, our study provides novel insight into the cell-type-specific roles of p53 and its downstream effectors in hematopoiesis using unique models of p53 hyperactivity induced by endogenous stress. We conclude that MYSM1 is a critical negative regulator of p53 transcriptional programs in hematopoiesis, and that its repression of Bbc3/PUMA expression is essential for MPP survival, and partly contributes to maintaining HSC function.
| S-EPMC4832099 | biostudies-literature
Project description:Dendritic cells (DCs) are the most significant antigen presenting cells of the immune system, critical for the activation of naïve T cells. The pathways controlling DC development, maturation, and effector function therefore require precise regulation to allow for an effective induction of adaptive immune response. MYSM1 is a chromatin binding deubiquitinase (DUB), known to act as an activator of gene expression via its catalytic activity for monoubiquitinated histone H2A (H2A-K119ub), which is a highly abundant repressive epigenetic mark. MYSM1 is an important regulator of hematopoiesis in mouse and human, and a systemic constitutive loss of Mysm1 in mice results in a depletion of many hematopoietic progenitors, including DC precursors, with the downstream loss of most DC lineage cells. However, the roles of MYSM1 at the later checkpoints in DC development, maturation, activation, and effector function at present remain unknown. In the current work, using a range of mouse models (Mysm1flCreERT2, Mysm1flCD11c-cre, Mysm1DN), we further the understanding of MYSM1 functions in the DC lineage: assessing the requirement for MYSM1 in DC development independently of other complex developmental phenotypes, exploring its role at the later checkpoints in DC maintenance and activation in response to microbial stimulation, and testing the requirement for the DUB catalytic activity of MYSM1 in these processes. Surprisingly, we demonstrate that MYSM1 expression and catalytic activity in DCs are dispensable for the maintenance of DC numbers in vivo or for DC activation in response to microbial stimulation. In contrast, MYSM1 and its DUB catalytic activity in hematopoietic progenitors are essential for normal DC development, and its loss results not only in a severe depletion of DC lineage cells, but also in the production of functionally altered DCs, with a dysregulation of many housekeeping transcriptional programs and significantly altered responses to microbial stimulation.
2024-01-31 | GSE236534 | GEO
Project description:MYSM1 is a transcriptional regulator essential for HSC function and hematopoiesis. We established that HSC dysfunction in Mysm1-deficiency is driven by p53 stress response, however, the molecular function of MYSM1 as a transcriptional activator and its essential role in p53 stress response repression remain difficult to reconcile. Here, we performed genome-wide analyses of MYSM1-regulated genes in hematopoietic stem and progenitor cells (HSPCs). This included RNA-Seq of sorted Mysm1-deficient mouse HSCs and MPPs, and ChIP-Seq mapping of MYSM1 DNA-binding sites in hematopoietic progenitor cell lines. We demonstrate a direct role for MYSM1 in the regulation of genes encoding protein components of the ribosome (RP-genes) and other regulators of translation. Mechanistically, the dysregulation of RP-genes in Mysm1-deficiency was upstream of p53-activation and associated with reduced HSCs protein synthesis rates and p53-dependent anemia.
2020-07-28 | GSE150663 | GEO
Project description:MYSM1 is a transcriptional regulator essential for HSC function and hematopoiesis. We established that HSC dysfunction in Mysm1-deficiency is driven by p53 stress response, however, the molecular function of MYSM1 as a transcriptional activator and its essential role in p53 stress response repression remain difficult to reconcile. Here, we performed genome-wide analyses of MYSM1-regulated genes in hematopoietic stem and progenitor cells (HSPCs). This included RNA-Seq of sorted Mysm1-deficient mouse HSCs and MPPs, and ChIP-Seq mapping of MYSM1 DNA-binding sites in hematopoietic progenitor cell lines. We demonstrate a direct role for MYSM1 in the regulation of genes encoding protein components of the ribosome (RP-genes) and other regulators of translation. Mechanistically, the dysregulation of RP-genes in Mysm1-deficiency was upstream of p53-activation and associated with reduced HSCs protein synthesis rates and p53-dependent anemia.
2020-07-28 | GSE150666 | GEO
Project description:Synthetic lethality is a powerful approach for targeting oncogenic drivers in cancer. Recent studies revealed that cancer cells with microsatellite instability (MSI) require Werner (WRN) helicase for survival; however, the underlying mechanism remains unclear. In this study, we found that WRN depletion strongly induced p53 and its downstream apoptotic target PUMA in MSI colorectal cancer (CRC) cells. p53 or PUMA deletion abolished apoptosis induced by WRN depletion in MSI CRC cells. Importantly, correction of MSI abrogated the activation of p53/PUMA and cell killing, while induction of MSI led to sensitivity in isogenic CRC cells. Rare p53-mutant MSI CRC cells are resistant to WRN depletion due to lack of PUMA induction, which could be restored by wildtype p53 knock-in or reconstitution. WRN depletion or treatment with the RecQ helicase inhibitor ML216 suppressed in vitro and in vivo growth of MSI CRCs in a p53/PUMA_x0002_dependent manner. ML216 treatment was efficacious in MSI CRC patient-derived xenografts (PDX). Interestingly, p53 gene remains wildtype in the majority of MSI CRCs. These results indicate a critical role of p53/PUMA-mediated apoptosis in the vulnerability of MSI CRCs to WRN loss, and support WRN as a promising therapeutic target in p53-wildtype MSI CRCs.
2022-10-26 | GSE216455 | GEO