Cohesin-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation

Chen, Ziyang; Amro, Elias; F, Becker; Hölzer, Martin; Rasa, Seyed Mohammad Mahdi; Njeru, Sospeter Ngoci; Han, Bing; Sanzo, Simone Di; Chen, Yulin; Tang, Duozhuang; Si, Ting; Haenold, Ronny; Groth, Marco; Romanov, Victor; Kirkpatrick, Joanna; Kraus, Johann M.; Kestler, Hans A.; Marz, Manja; Ori, Alessandro; Neri, Francesco; Morita, Yohei; Rudolph, K. Lenhard

doi:10.1084/jem.20181505

Cited by 59 publications

(59 citation statements)

References 88 publications

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“…Cohesins are involved in sister chromatid cohesion, formation of topologically associated domains and in long-range enhancer/promoter interactions (Kagey et al, 2010;Newkirk et al, 2017). Furthermore, cohesin binding can inhibit repressive histone modifications (Misulovin et al, 2008;Schaaf et al, 2013) and cohesin knockdown can increase repressive chromatin in hematopoietic stem and progenitor cells (Chen et al, 2018). Our findings in NBs strongly support a role for cohesin in controlling the chromatin landscape.…”

Section: Cohesin As a Regulator Of Cell Deathsupporting

confidence: 67%

A Cut/cohesin axis alters the chromatin landscape to facilitate neuroblast death

et al. 2019

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Precise control of cell death in the nervous system is essential for development. Spatial and temporal factors activate the death of Drosophila neural stem cells (neuroblasts) by controlling the transcription of multiple cell death genes through a shared enhancer. The activity of this enhancer is controlled by abdominal A and Notch, but additional inputs are needed for proper specificity. Here, we show that the Cut DNA binding protein is required for neuroblast death, regulating reaper and grim downstream of the shared enhancer and of abdominal A expression. The loss of cut accelerates the temporal progression of neuroblasts from a state of low overall levels of H3K27me3 to a higher H3K27me3 state. This is reflected in an increase in H3K27me3 modifications in the cell death gene locus in the CNS on Cut knockdown. We also show that cut regulates the expression of the cohesin subunit Stromalin. Stromalin and the cohesin regulatory subunit Nipped-B are required for neuroblast death, and knockdown of Stromalin increases H3K27me3 levels in neuroblasts. Thus, Cut and cohesin regulate apoptosis in the developing nervous system by altering the chromatin landscape.

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Section: Cohesin As a Regulator Of Cell Deathsupporting

confidence: 67%

A Cut/cohesin axis alters the chromatin landscape to facilitate neuroblast death

et al. 2019

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“…Cohesindependent NF-κB signaling results in stem cell differentiation. Accordingly, increases in inflammation or aging-induced NF-κB signaling were found to promote the selection of subpopulations of HSCs with reduced cohesin expression, thus being resistant to inflammation-induced loss of differentiation and self-renewal [41]. Since cohesin expression is reduced in myeloid-biased HSCs, this selection appears to contribute to the myeloid skewing of hematopoiesis during aging, which is associated with the induction of myeloid differentiation programs in inflammation-exposed HSCs [51].…”

Section: Inflammatory Signaling In Aged Stem Cellsmentioning

confidence: 99%

“…Endotoxin exposure and NF-κB inductionan important signaling axis in response to bacterial infectionhave been reported to affect the function of HSCs in a way that mimics HSC aging, with a reduction in repopulation capacity and a shift towards myeloid differentiation [39,40]. Interestingly, HSCs from old mice display elevated expression of inflammatory markers and increased NF-κB signaling activity [41,42]. It remains to be analyzed whether intestinal barrier defects and/or microbiota dysbiosis contribute to this phenotype of HSC aging.…”

Section: Inflammatory Signaling In Aged Stem Cellsmentioning

confidence: 99%

“…Along these lines, there is evidence that chronic inflammation selects for subpopulations of stem cells with an altered chromatin structure resulting in inflammation resistance coupled with changes in gene transcription and differentiation defects. Specifically, studies on aging mice revealed evidence that the cohesin complex mediates NF-κB signaling in HSCs in response to inflammation [41]. Cohesindependent NF-κB signaling results in stem cell differentiation.…”

Section: Inflammatory Signaling In Aged Stem Cellsmentioning

confidence: 99%

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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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“…Interestingly, http://bmbreports.org BMB Reports recent studies have revealed, using single-cell transplantation and lineage-tracing technology, that hematopoiesis of defined HSCs and HPCs proceeded heterogeneously, which indicates that cells have subtypes and preferences to differentiate into a particular type of blood cell; lineage priming (69,70). Functionally impaired hematopoiesis is a hallmark of the aging process, as is a remarkably decreased self-renewal capacity of HSCs (71). Of note, hematopoietic changes with advancing age are intimately related to inflammaging, which includes depression in both the adaptive and the innate immune system, vulnerability to infections, spontaneous development of autoimmune diseases, and hematopoietic malignancies (72).…”

Section: Inflammaging Of Bm Niche Accelerates Skewed Blood-cell Diffementioning

confidence: 99%

Impact of Mesenchymal Stem Cell Senescence on Inflammaging

Lee

2020

BMB Rep.

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Life expectancy has dramatically increased around the world over the last few decades, and staying healthier longer, without chronic disease, has become an important issue. Although understanding aging is a grand challenge, our understanding of the mechanisms underlying the degeneration of cell and tissue functions with age and its contribution to chronic disease has greatly advanced during the past decade. As our immune system alters with aging, abnormal activation of immune cells leads to imbalance of innate and adaptiveimmunity and develops a persistent and mild systemic inflammation, inflammaging. With their unique therapeutic properties, such as immunomodulation and tissue regeneration, mesenchymal stem cells (MSCs) have been considered to be a promising source for treating autoimmune disease or as anti-aging therapy. Although direct evidence of the role of MSCs in inflammaging has not been thoroughly studied, features reported in senescent MSCs or the aging process of MSCs are associated with inflammaging; MSC niche-driven skewing of hematopoiesis toward the myeloid lineage or oncogenesis, production of pro-inflammatory cytokines, and weakening their modulative property on macrophage polarization, which plays a central role on inflammaging development. This review explores the role of senescent MSCs as an important regulator for onset and progression of inflammaging and as an effective target for anti-aging strategies. [BMB Reports 2020; 53(2): 65-73] BMB Rep. 2020; 53(2): 65-73

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Cohesin-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation

Cited by 59 publications

References 88 publications

A Cut/cohesin axis alters the chromatin landscape to facilitate neuroblast death

A Cut/cohesin axis alters the chromatin landscape to facilitate neuroblast death

Quiescence: Good and Bad of Stem Cell Aging

Impact of Mesenchymal Stem Cell Senescence on Inflammaging

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