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688dc1e8-1e79-440c-8d4b-107d0e08f013 - samples

ABSTRACT: We show that lysosomes are antagonistically controlled by TFEB and MYC to balance catabolic and anabolic processes required for activating LT-HSC and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway for membrane receptor degradation limits LT-HSC metabolic and mitogenic activation; this promotes quiescence and self-renewal and governs erythroid-myeloid commitment. By contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism to drive LT-HSC activation. Collectively, our study identifies lysosomes as a central regulatory hub for proper and coordinated stem cell fate determination.

PROVIDER: EGAD00001006884 | EGA |

REPOSITORIES: EGA

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Stem cell fate choices are regulated through antagonistic control of lysosomes by MYC and TFEB [RNA-Seq 5]

Project description:We show that lysosomes are antagonistically controlled by TFEB and MYC to balance catabolic and anabolic processes required for activating LT-HSC and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway for membrane receptor degradation limits LT-HSC metabolic and mitogenic activation; this promotes quiescence and self-renewal and governs erythroid-myeloid commitment. By contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism to drive LT-HSC activation. Collectively, our study identifies lysosomes as a central regulatory hub for proper and coordinated stem cell fate determination.

2021-07-31 | GSE153915 | GEO

Stem cell fate choices are regulated through antagonistic control of lysosomes by MYC and TFEB [RNA-Seq 3]

2021-07-31 | GSE153913 | GEO

Stem cell fate choices are regulated through antagonistic control of lysosomes by MYC and TFEB [RNA-Seq 1]

2021-07-31 | GSE153911 | GEO

Stem cell fate choices are regulated through antagonistic control of lysosomes by MYC and TFEB [ATAC-Seq]

2021-07-31 | GSE153910 | GEO

Stem cell fate choices are regulated through antagonistic control of lysosomes by MYC and TFEB [RNA-Seq 4]

2021-07-31 | GSE153914 | GEO

Stem cell fate choices are regulated through antagonistic control of lysosomes by MYC and TFEB [RNA-Seq 2]

2021-07-31 | GSE153912 | GEO

The transition from quiescent to activated states in human hematopoietic stem cells is governed by dynamic 3D genome reorganization [Low-C]

Project description:Life-long blood production requires long-term hematopoietic stem cells (LT-HSC) - marked by stemness states involving quiescence and self-renewal - to transition into activated short-term HSC (ST-HSC) with reduced stemness. As few transcriptional changes underlie this transition, we used single-cell and bulk ATAC-seq on human HSC and stem/progenitor subsets (HSPC) to uncover chromatin accessibility signatures, one including LT-HSC (LT/HSPC signature) and another excluding LT-HSC (Act/HSPC signature). These signatures inversely correlated during early hematopoietic commitment and differentiation. The Act/HSPC signature contains CTCF binding sites mediating 351 chromatin interactions, engaged in ST-HSC but not LT-HSC, enclosing multiple stemness pathway genes active in LT-HSC and repressed in ST-HSC. CTCF silencing derepressed stemness genes, restraining quiescent LT-HSC from transitioning to activated ST-HSC. Hence, 3D chromatin interactions centrally mediated by CTCF, endow a gatekeeper function that governs the earliest fate transitions HSC make by coordinating disparate stemness pathways linked to quiescence and self-renewal.

2020-11-23 | GSE159287 | GEO

ChIP-Seq of TFEB in LT-HSC

Project description:ChIP-Seq of TFEB in LT-HSC

| EGAS00001005462 | EGA

Combined single-cell tracking and omics improves blood stem cell fate regulator identification

Project description:HSCs can undergo asymmetric lysosomal division, marking the daughter receiving less lysosomes for metabolic activation and its corresponding sister for quiescence (Loeffler et al. 2019, Nature). We use scRNA-Seq to trace the earliest fate regulators controlling this fate divergence in HSC daughter cells. Methods: We use quantitative time-lapse imaging of murine HSCs to detect their first in-vitro division. Cells are isolated with a micromanipulator and submitted to Smart-Seq2 RNA sequencing. Single-end reads were mapped to the M 21 release mouse genome using STAR aligner. Raw Counts are extracted with featureCounts. Results: We successfully isolated 474 high-quality single cell transcriptomes from HSC daughter cells and mapped their transcriptional profiles to the observed inheritance.

2022-08-15 | GSE167317 | GEO

Mitochondrial hetereogeneity in hematopoietic stem cells (HSC)

Project description:Quiescence is a fundamental property that maintains hematopoietic stem cells (HSCs)’ potency throughout life. Quiescent HSCs are thought to rely on glycolysis for their energy but the overall metabolic properties of HSCs remain incompletely understood. Using combined approaches including single cell RNA-Seq we show that mitochondrial membrane potential (MMP) distinguishes the quiescent from cycling-primed HSCs. We found that primed but not quiescent HSCs relied readily on glycolysis. Notably, in vivo inhibition of glycolysis robustly enhanced the competitive repopulation ability of primed HSCs. We further show that HSC quiescence is maintained by an abundance of large lysosomes. Repression of lysosomal activation led to further enlargement of lysosomes, while repressing mTOR activation and glucose uptake. This also induced increased lysosomal sequestration of mitochondria and enhanced the competitive repopulation ability of primed HSCs by over 90-fold in vivo. These findings show that restraining lysosomal activity is key in preserving HSC quiescence and potency, and may be therapeutically relevant.

2020-03-05 | GSE141457 | GEO

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