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SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [hMeDIP-Seq]

ABSTRACT: SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [hMeDIP-Seq]

PROVIDER: PRJNA481884 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7540950.fastq.gz	Fastqsanger.gz
	SRR7540951.fastq.gz	Fastqsanger.gz
	SRR7540952.fastq.gz	Fastqsanger.gz
	SRR7540953.fastq.gz	Fastqsanger.gz
	SRR7540948.fastq.gz	Fastqsanger.gz

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SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [hMeDIP-Seq]

2018-08-13 | GSE117363 | GEO

SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function

Project description:SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function

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SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [microarray expression profiling]

Project description:Improved understanding of mechanisms regulating myelodysplastic syndrome (MDS) hematopoietic stem/progenitor cell (HSPC) growth and self-renewal is critical for developing MDS therapy. We revealed a novel regulatory axis that SIRT1-deficiency induced TET2 hyperacetylation promotes MDS HSPC functions, and provide an approach to target MDS HSPCs by activating SIRT1 deacetylase. Four Groups: Group1: MDS-L cells transduced with lentiviral vector targeting non-silence squence (control shRNA for SIRT1); Group2: MDS-L cells transduced with lentiviral vector containing interference squence targeting SIRT1 (SIRT shRNA); Group 3: MDS-L cells transduced with lentiviral vector targeting non-silence squence (control shRNA for TET2); Group 4: MDS-L cells transduced with lentiviral vector containing interference squence targeting TET2 (TET2 shRNA).

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SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [microarray expression profiling]

Project description:SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function [microarray expression profiling]

| PRJNA481584 | ENA

SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function.

Project description:Myelodysplastic syndrome (MDS), a largely incurable hematological malignancy, is derived from aberrant clonal hematopoietic stem/progenitor cells (HSPCs) that persist after conventional therapies. Defining the mechanisms underlying MDS HSPC maintenance is critical for developing MDS therapy. The deacetylase SIRT1 regulates stem cell proliferation, survival, and self-renewal by deacetylating downstream proteins. Here we show that SIRT1 protein levels were downregulated in MDS HSPCs. Genetic or pharmacological activation of SIRT1 inhibited MDS HSPC functions, whereas SIRT1 deficiency enhanced MDS HSPC self-renewal. Mechanistically, the inhibitory effects of SIRT1 were dependent on TET2, a safeguard against HSPC transformation. SIRT1 deacetylated TET2 at conserved lysine residues in its catalytic domain, enhancing TET2 activity. Our genome-wide analysis identified cancer-related genes regulated by the SIRT1/TET2 axis. SIRT1 activation also inhibited functions of MDS HSPCs from patients with TET2 heterozygous mutations. Altogether, our results indicate that restoring TET2 function through SIRT1 activation represents a promising means to target MDS HSPCs.

| S-EPMC6143172 | biostudies-literature

SIRT1 Activation Disrupts Maintenance of Myelodysplastic Syndrome Stem and Progenitor Cells by Restoring TET2 Function

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-08-13 | GSE117383 | GEO

A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome

Project description:A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome

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A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome (RNA-Seq)

Project description:A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome (RNA-Seq)

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LARP7 ameliorates cellular senescence and aging-related atherosclerosis by allosterically enhancing SIRT1 deacetylase activity

Project description:Cell senescence is a cell state characterized with permanent cell cycle arrest and elevated proinflammatory secretome and associated with pleiotropic essential physiopathological processes. The persistent DNA damage response (DDR) is the major stress leading to senescence, however the molecular mechanism underling remains elusive. Here, we identified the La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as a novel SIRT1 deacetylase activator. It directly interacted with SIRT1 allosteric regulatory domain and enhanced its deacetylase activity. DDR-mediated ATM activation trigged the extracellular shuttling and downregulation of LARP7 that dampened the SIRT1 deacetylase activity and enhanced p53 and NFB (p65) transcriptional activity by augmenting their acetylation. As a consequence, activated p53 and NFB arrested cell growth and promoted SASP genes expression, and thereby accelerated the cellular senescence. Inducible deletion of LARP7 in wildtype mouse led to senescent cell accumulation and premature ageing. Furthermore, we identified that ATM-LARP7-SIRT1-p53/NFB senescent axis was active in the aortic senescence and atherogenesis. Genetic depletion of LARP7 aggravated the atherogenesis but conversely, inhibited ATM activation or restoring LARP7 expression with genetic manipulation alleviated the vascular aging and atherogenesis. Together, this study identifies LARP7 as a novel SIRT1 cellular activator and it’s-mediated ATM-LARP7-SIRT1-p53/NFB axis is attributed to DDR-mediated cellular senescence and aging-related pathologies.

2021-10-30 | GSE160279 | GEO

Sirt1 targeting promotes Treg function

Project description:Sirtuin-1 (Sirt1), a class III histone/protein deacetylase is central to cellular metabolism, stress responses and aging, but its contributions to various host immune functions have been little investigated. To study the role of Sirt1 in T-cell functions, we undertook targeted deletions by mating mice with a floxed Sirt1 gene to mice expressing CD4-cre or Foxp3-cre recombinase, respectively. We found that Sirt1 deletion left conventional T-effector cell activation, proliferation and cytokine production largely unaltered. However, Sirt1 targeting promoted the expression and acetylation of Foxp3, a key transcription factor in T-regulatory (Treg) cells, and increased Treg suppressive functions in vitro and in vivo. Consistent with these data, mice with targeted deletions of Sirt1 in either CD4+ T-cells or Foxp3+ Treg cells exhibited prolonged survival of MHC-mismatched cardiac allografts. Allografts in Sirt1 targeted recipients showed long-term preservation of myocardial histology and infiltration by Foxp3+ Treg cells. Comparable results were seen in wild-type allograft recipients treated with Sirt1 inhibitors, such as EX-527 and splitomicin. Hence, Sirt1 may inhibit Treg functions and its targeting may have therapeutic value in autoimmunity and transplantation.

2011-01-05 | GSE26425 | GEO

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