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T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1 [bulkRNA]

ABSTRACT: T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1 [bulkRNA]

PROVIDER: PRJNA474666 | ENA |

REPOSITORIES: ENA

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T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1 [bulkRNA]

Project description:Leukemia stem cells (LSCs) are regarded as the origins and key therapeutic targets of leukemia, but limited knowledge is available on the key determinants of LSC “stemness”. Using single cell RNAseq analysis, we identify a master regulator PU.1, whose LSC-specific expression determines the molecular signature and activity of LSC in the Pten-null T-ALL model. Although initiated by PTEN controlled β-catenin activation, PU.1 expression and LSC “stemness” are maintained by a β-catenin-PU.1-TIM-3 feedback loop, independent of the leukemogenic driver mutation. Perturbing any component of this loop, either genetically or pharmacologically, can prevent LSC formation or eradicate existing LSCs. LSCs lose their “stemness” when PU.1 expression is silenced by DNA methylation, which can be reactivated by 5-AZ. Importantly similar regulatory mechanisms are also present in human T-ALLs.

2018-11-17 | GSE115346 | GEO

T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1 [BiSulfite-seq]

2018-11-17 | GSE115316 | GEO

T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1 [scRNA-seq]

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T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1

Project description:T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1

| PRJNA474680 | ENA

T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1 [BiSulfite-seq]

Project description:T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1 [BiSulfite-seq]

| PRJNA474659 | ENA

T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1 [scRNA-seq]

Project description:T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1 [scRNA-seq]

| PRJNA474678 | ENA

T-ALL Leukemia Stem Cell “stemness” is Epigenetically Controlled by the Master Regulator PU.1

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

2018-11-17 | GSE115356 | GEO

KDM4C epigenetically regulates and forms a feed-forward loop with ALDH1A3 to maintain gastric cancer stemness

Project description:Gastric cancer (GC) stem cells (GCSCs) are characterized as high level of ALDH activity, however, the mechanisms of maintenance of high ALDH activity and stemness in GCSCs are largely unknown. Here, we report that KDM4C, a H3K9me2/3-demethylase, epigenetically regulates ALDH1A3 by histone demethylation and forms a feed-forward loop with ALDH1A3 to supports GS stemness. Ectopic expression of both KDM4C and ALDH1A3 promotes the properties of GCSCs, including spherogenecity, self-renewal, CD44 expression and ALDH activity; knockdown of anyone abolished the effect of each other. KDM4C directly binds to the promoter of ALDH1A3, leads to histone demethylation, thereby promoting ALDH1A3 transcription. Upregulated ALDH1A3 in turn transcriptionally upregulates KDM4C. Simultaneous inhibition of KDM4C and ALDH1A3 synergistically sensitizes GC sphere-derived cells to traditional chemotherapeutic drugs. The finding that upregulated ALDH1A3 promotes its own transcription via KDM4C-mediated epigenetic modification represents an important feed-forward mechanism for GCSCs to maintain stemness and promote tumourigenesis and our work thus suggests a novel therapeutic strategy for eradicating human GCSCs. To investigate the mechanisms underlying KDM4C promoting CG stemness, we identified the differentially expressed proteins (DEPs) between KDM4C-overexpressing and control AGS cells by iTRAQ-based quantitative proteomic analysis.

2022-02-16 | PXD023455 | Pride

T-ALL leukemia stem cell 'stemness' is epigenetically controlled by the master regulator SPI1.

Project description: Not available

| S-EPMC6251627 | biostudies-literature

The hematopoietic master transcription factor PU.1 requires its interaction with the SWI/SNF remodeler to access chromatin de novo

Project description:PU.1 is a prototype master transcription factor (TF) of hematopoietic cell differentiation with diverse roles in different lineages. Analysis of its genome-wide binding pattern across PU.1 expressing cell types revealed manifold cell type-specific binding patterns. They are not consistent with the epigenetic and chromatin constraints to PU.1 binding observed in vitro, suggesting that PU.1 requires auxiliary factors to access DNA in vivo. Using a model of transient mRNA expression we show that PU.1 induction leads to the extensive remodeling of chromatin, redistribution of partner transcription factors and rapid initiation of a myeloid gene expression program in heterologous cell types. By probing PU.1 mutants for defects in chromatin access and screening for PU.1 proximal proteins in vivo, we found that its N-terminal acidic domain was required for the recruitment of SWI/SNF remodeling complexes, de novo chromatin access and stable binding as well as the redistribution of partner TFs.

2019-11-20 | PXD013167 | Pride

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