Rb family proteins enforce the homeostasis of quiescent hematopoietic stem cells by repressing Socs3 expression

Kim, Eunsun; Cheng, Ying; Bolton-Gillespie, Elisabeth; Cai, Xiongwei; Ma, Connie; Tarangelo, Amy; Le, Linh; Jambhekar, Madhumita; Raman, Pichai; Hayer, Katharina E.; Wertheim, Gerald; Speck, Nancy A.; Tong, Wei; Viatour, Patrick

doi:10.1084/jem.20160719

Cited by 13 publications

(9 citation statements)

References 35 publications

(52 reference statements)

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“…These include stem cell-intrinsic signaling pathways and epigenetic regulators as well as components of the micromilieu and the blood-circulatory environment [7][8][9]. Overarching principles of quiescence maintenance have been identified involving the expression of cell cycle inhibitors like p21 and p57 [10][11][12] as well as tumor suppressor genes like RB and p53 [13][14][15][16] in stem cells of different organs/tissues ( Figure 1).…”

Section: Regulation Of Quiescencementioning

confidence: 99%

Quiescence: Good and Bad of Stem Cell Aging

Tümpel

Rudolph

2019

Trends in Cell Biology

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Stem cells are required for lifelong homeostasis and regeneration of tissues and organs in mammals, but the function of stem cells declines during aging. To preserve stem cells during life, they are kept in a quiescent state with low metabolic and low proliferative activity. However, activation of quiescent stem cellsan essential process for organ homeostasis/regenerationrequires concerted and faithful regulation of multiple molecular circuits controlling biosynthetic processes, repair mechanisms, and metabolic activity. Thus, while protecting stem cell maintenance, quiescence comes at the cost of vulnerability during the process of stem cell activation. Here we discuss molecular and biochemical processes regulating stem cells' maintenance in and exit from quiescence and how age-related failures of these circuits can contribute to organism aging. Highlights The quiescence stage of stem cells has beneficial and adverse effects on stem cell aging.

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Section: Regulation Of Quiescencementioning

confidence: 99%

Quiescence: Good and Bad of Stem Cell Aging

Tümpel

Rudolph

2019

Trends in Cell Biology

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“…35,37 We also found that Jmjd6 deficiency results in upregulation of other pathways whose activity is known to deplete or exhaust HSCs, including mTORC1 signaling, 39 protein synthesis, 40 and E2F downstream pathway. 41 Notably, although our findings reveal JMJD6 as a suppressor of multiple pathways, whose excessive activation promotes HSC failure, the mechanisms through which JMJD6 functions in this context remain an open question, meriting further investigations. Finally, we revealed that JMJD6 is unlikely to be a major splicing regulator in HSCs.…”

Section: Discussionmentioning

confidence: 80%

“…To mechanistically understand the failure of Jmjd6-deficient HSCs upon serial transplantation, we examined the molecular signature of Jmjd6-deficient LSK cells. Although differential gene expression analysis identified a number of individual deregulated genes (supplemental Figure 4), GSEA indicated a broader upregulation of processes detrimental to HSCs, including p53 activity 35,37 (which is known to be directly repressed by JMJD6 7,17 ), G 1 /S and G 2 /M checkpoints, OXPHOS, 38 mTORC1 signaling, 39 protein synthesis, 40 and E2F signaling 41 (Figure 4A-B). Given that suppression of OXPHOS is essential for HSC self-renewal, and its upregulation devastates HSC functions, 38 we validated the impact of Jmjd6 deletion on OXPHOS using a Seahorse XF Analyzer.…”

Section: Jmjd6 Suppresses Oxphos and Ros Generation To Control Hematopoiesismentioning

confidence: 99%

JMJD6 promotes self-renewal and regenerative capacity of hematopoietic stem cells

et al. 2021

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Lifelong multilineage hematopoiesis critically depends on rare hematopoietic stem cells (HSCs) that reside in the hypoxic bone marrow microenvironment. Although the role of the canonical oxygen sensor hypoxia-inducible factor prolyl hydroxylase has been investigated extensively in hematopoiesis, the functional significance of other members of the 2-oxoglutarate (2-OG)-dependent protein hydroxylase family of enzymes remains poorly defined in HSC biology and multilineage hematopoiesis. Here, by using hematopoietic-specific conditional gene deletion, we reveal that the 2-OG–dependent protein hydroxylase JMJD6 is essential for short- and long-term maintenance of the HSC pool and multilineage hematopoiesis. Additionally, upon hematopoietic injury, Jmjd6-deficient HSCs display a striking failure to expand and regenerate the hematopoietic system. Moreover, HSCs lacking Jmjd6 lose multilineage reconstitution potential and self-renewal capacity upon serial transplantation. At the molecular level, we found that JMJD6 functions to repress multiple processes whose downregulation is essential for HSC integrity, including mitochondrial oxidative phosphorylation (OXPHOS), protein synthesis, p53 stabilization, cell cycle checkpoint progression, and mTORC1 signaling. Indeed, Jmjd6-deficient primitive hematopoietic cells display elevated basal and maximal mitochondrial respiration rates and increased reactive oxygen species (ROS), prerequisites for HSC failure. Notably, an antioxidant, N-acetyl-l-cysteine, rescued HSC and lymphoid progenitor cell depletion, indicating a causal impact of OXPHOS-mediated ROS generation upon Jmjd6 deletion. Thus, JMJD6 promotes HSC maintenance and multilineage differentiation potential by suppressing fundamental pathways whose activation is detrimental for HSC function.

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“…Gene set enrichment analysis (GSEA) indicated a broad dysregulation of multiple pathways and processes, which was compatible with the loss of HSC function. Notably, we found that Cited2-deficient HSCs displayed activation of proinflammatory pathways, c-MYC and E2F targets, and K-RAS and mTORC1 signaling, whose elevated activity is known to lead to HSC exhaustion or loss of their reconstitution potential (Kim et al, 2017;Pietras, 2017;Sasine et al, 2018;Wilson et al, 2004;Yilmaz et al, 2006) (Figures 5B and 5C). Consistent with upregulation of E2F and c-MYC targets, analysis of proximal promoters of upregulated genes revealed the presence of E2F and c-MYC motifs, suggesting that CITED2 may repress E2Fs and c-MYC (Figure 5D).…”

Section: Cited2 Maintains Hscs By Regulating Mcl1 Expressionmentioning

confidence: 99%