Similar Datasets
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:Endocrine resistance is a crucial challenge in estrogen receptor alpha (ERa)-positive breast cancer (BCa). Aberrant alteration in modulation of E2/ERa signaling pathway has emerged as the putative contributor for endocrine resistance in BCa. Herein, we demonstrate that MYSM1 as a deubiquitinase participates in modulating ERa action via histone and non-histone deubiquitination. MYSM1 is involved in maintenance of ERa stability via ERa deubiquitination. Silencing MYSM1 induces enhancement of histone H2A ubiquitination as well as reduction of histone H3K4me3, H3K9ac and H3K27ac levels at cis regulatory elements on promoter of ERa-regulated genes. ChIP-seq analysis indicate that the half-EREs are the significant enrichment sites for MYSM1 on ERa-regulated genes. MYSM1 depletion attenuates cell growth in BCa-derived cell lines and xenograft models. Knockdown of MYSM1 increases the sensitivity of antiestrogen agents in BCa cells. A virtual screen shows that the small molecule Imatinib could potentially interact with catalytic MPN domain of MYSM1 to inhibit BCa cell growth via MYSM1-ERa axis. MYSM1 is highly expressed in clinical BCa samples, especially in aromatase inhibitor (AI) non-responsive tissues. These findings clarify the molecular mechanism of MYSM1 as an epigenetic modifier in regulation of ERa action and provide a potential therapeutic target for endocrine resistance in BCa.
2023-08-08 | GSE240215 | GEO
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: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: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:We performed chromatin immunoprecipitation according to standard protocols. Mouse embryonic stem cells were treated with formaldehyde to cross-link proteins to DNA. Cell lysates were sonicated to break up DNA. The histone deubiquitinase Mysm1 was then immunoprecipitated from the sonicated cell lysates. Mysm1-bound (and control antibody-bound) DNA fragments were purified after proteinase K treatment and cross-link reversal. Input DNA was purified directly from the sonicated cell lysates. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
2015-11-03 | E-ERAD-398 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE34282: Effects of Mysm1 deficiency on gene expression across a range of mouse tissues and cell types (tissue data) GSE34284: Effects of Mysm1 deficiency on gene expression across a range of mouse tissues and cell types (cell data) Refer to individual Series
2012-01-01 | E-GEOD-34285 | biostudies-arrayexpress
Project description:Stem cell differentiation and lineage specification depend on coordinated programs of gene expression, but our knowledge of the chromatin modifying factors regulating these events remains incomplete. Ubiquitination of histone H2A (H2A-K119u) is a common chromatin modification associated with gene silencing, and controlled by the ubiquitin-ligase polycomb repressor complex 1 (PRC1) and H2A-deubiquitinating enzymes (H2A-DUBs). The roles of H2A-DUBs in mammalian development, stem cells, and haematopoiesis have not been addressed. Here we characterized an H2A-DUB targeted mouse line Mysm1-tm1a/tm1a and demonstrated defects in bone marrow haematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis. Development of lymphocytes was impaired from the earliest stages of their differentiation; and there was also a depletion of erythroid cells and a defect in erythroid progenitor function. These phenotypes were due to a cell-intrinsic requirement for Mysm1 in the bone marrow. Importantly, Mysm1-tm1a/tm1a haematopoietic stem cells were functionally impaired, and this was associated with elevated levels of reactive oxygen species, γH2AX DNA damage marker, and p53 protein in the haematopoietic progenitors. Overall these data establish a role for Mysm1 in the maintenance of bone marrow stem cell function, in the control of oxidative stress and genetic stability in haematopoietic progenitors, and in the development of lymphoid and erythroid lineages. Total RNA from different mouse tissues (liver, bone marrow, brain) and cell types (embryonic fibroblasts - MEFs, and embryonic stem cells - ESCs) from wild type, Mysm1+/tm1a (heterozygous), and Mysm1tma1/tm1a (homozygous) mice was analyzed. Tissue and MEFs comparisons are between 3-4 animals per group; ESC comparisons are between three independently passaged samples of wild type, Mysm1+/tm1a, and Mysm1tma1/tm1aES-cells, all on C57BL/6 background. Full allele name: Mysm1tm1a(KOMP)WTSI . This Series includes the data from the tissues.
2012-01-01 | E-GEOD-34282 | biostudies-arrayexpress
Project description:Stem cell differentiation and lineage specification depend on coordinated programs of gene expression, but our knowledge of the chromatin modifying factors regulating these events remains incomplete. Ubiquitination of histone H2A (H2A-K119u) is a common chromatin modification associated with gene silencing, and controlled by the ubiquitin-ligase polycomb repressor complex 1 (PRC1) and H2A-deubiquitinating enzymes (H2A-DUBs). The roles of H2A-DUBs in mammalian development, stem cells, and haematopoiesis have not been addressed. Here we characterized an H2A-DUB targeted mouse line Mysm1-tm1a/tm1a and demonstrated defects in bone marrow haematopoiesis, resulting in lymphopenia, anemia, and thrombocytosis. Development of lymphocytes was impaired from the earliest stages of their differentiation; and there was also a depletion of erythroid cells and a defect in erythroid progenitor function. These phenotypes were due to a cell-intrinsic requirement for Mysm1 in the bone marrow. Importantly, Mysm1-tm1a/tm1a haematopoietic stem cells were functionally impaired, and this was associated with elevated levels of reactive oxygen species, γH2AX DNA damage marker, and p53 protein in the haematopoietic progenitors. Overall these data establish a role for Mysm1 in the maintenance of bone marrow stem cell function, in the control of oxidative stress and genetic stability in haematopoietic progenitors, and in the development of lymphoid and erythroid lineages. Total RNA from different mouse tissues (liver, bone marrow, brain) and cell types (embryonic fibroblasts - MEFs, and embryonic stem cells - ESCs) from wild type, Mysm1+/tm1a (heterozygous), and Mysm1tma1/tm1a (homozygous) mice was analyzed. Tissue and MEFs comparisons are between 3-4 animals per group; ESC comparisons are between three independently passaged samples of wild type, Mysm1+/tm1a, and Mysm1tma1/tm1aES-cells, all on C57BL/6 background. Full allele name: Mysm1tm1a(KOMP)WTSI . This Series includes the data from the cells.
2012-01-01 | E-GEOD-34284 | biostudies-arrayexpress
Project description:To investigate differential gene expression of CD34+CD45RA-CD90+ cells with MYSM1 deficiency achieved by CRISPR editing
2023-02-17 | GSE221169 | GEO