Epigenetic regulation of adult stem cell function

A healthy diet improves adult stem cell function and delays diseases such as cancer, heart disease, and neurodegeneration. Defining molecular mechanisms by which nutrients dictate stem cell behavior is a key step toward understanding the role of diet in tissue homeostasis. In this paper, we elucidate the mechanism by which dietary cholesterol controls epithelial follicle stem cell (FSC) proliferation in the fly ovary. In nutrient-restricted flies, the transmembrane protein Boi sequesters Hedgehog (Hh) ligand at the surface of Hh-producing cells within the ovary, limiting FSC proliferation. Upon feeding, dietary cholesterol stimulates S6 kinase–mediated phosphorylation of the Boi cytoplasmic domain, triggering Hh release and FSC proliferation. This mechanism enables a rapid, tissue-specific response to nutritional changes, tailoring stem cell divisions and egg production to environmental conditions sufficient for progeny survival. If conserved in other systems, this mechanism will likely have important implications for studies on molecular control of stem cell function, in which the benefits of low calorie and low cholesterol diets are beginning to emerge.

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The BAF53a subunit of SWI/SNF-like BAF complexes is essential for hemopoietic stem cell function

Blood ◽

10.1182/blood-2012-04-427047 ◽

2012 ◽

Vol 120 (24) ◽

pp. 4720-4732 ◽

Cited By ~ 62

Author(s):

Veneta Krasteva ◽

Manuel Buscarlet ◽

Abigail Diaz-Tellez ◽

Marie-Anne Bernard ◽

Gerald R. Crabtree ◽

...

Keyword(s):

Stem Cell ◽

Chromatin Remodeling ◽

Progenitor Cell ◽

Cell Function ◽

Adult Stem Cell ◽

Hemopoietic Stem Cell ◽

Conditional Deletion ◽

Chromatin Remodeling Complexes ◽

A Subunit

Abstract ATP-dependent SWI/SNF-like BAF chromatin remodeling complexes are emerging as key regulators of embryonic and adult stem cell function. Particularly intriguing are the findings that specialized assemblies of BAF complexes are required for establishing and maintaining pluripotent and multipotent states in cells. However, little is known on the importance of these complexes in normal and leukemic hemopoiesis. Here we provide the first evidence that the actin-related protein BAF53a, a subunit of BAF complexes preferentially expressed in long-term repopulating stem cells, is essential for adult hemopoiesis. Conditional deletion of BAF53a resulted in multilineage BM failure, aplastic anemia, and rapid lethality. These severe hemopoietic defects originate from a proliferative impairment of BM HSCs and progenitors and decreased progenitor survival. Using hemopoietic chimeras, we show that the impaired function of BAF53a-deficient HSCs is cell-autonomous and independent of the BM microenvironment. Altogether, our studies highlight an unsuspected role for BAF chromatin remodeling complexes in the maintenance of HSC and progenitor cell properties.

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Aldehyde dehydrogenase 1a1 is dispensable for stem cell function in the mouse hematopoietic and nervous systems

Blood ◽

10.1182/blood-2008-05-156752 ◽

2009 ◽

Vol 113 (8) ◽

pp. 1670-1680 ◽

Cited By ~ 70

Author(s):

Boaz P. Levi ◽

Ömer H. Yilmaz ◽

Gregg Duester ◽

Sean J. Morrison

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Aldehyde Dehydrogenase ◽

Cell Function ◽

Hematopoietic Cells ◽

Adult Stem Cell ◽

Aldh Activity ◽

Hematopoietic Stem ◽

Nervous Systems ◽

Adult Mice

Abstract High levels of aldehyde dehydrogenase (ALDH) activity have been proposed to be a common feature of stem cells. Adult hematopoietic, neural, and cancer stem cells have all been reported to have high ALDH activity, detected using Aldefluor, a fluorogenic substrate for ALDH. This activity has been attributed to Aldh1a1, an enzyme that is expressed at high levels in stem cells and that has been suggested to regulate stem cell function. Nonetheless, Aldh1a1 function in stem cells has never been tested genetically. We observed that Aldh1a1 was preferentially expressed in mouse hematopoietic stem cells (HSCs) and expression increased with age. Hematopoietic cells from Aldh1a1-deficient mice exhibited increased sensitivity to cyclophosphamide in a non–cell-autonomous manner, consistent with its role in cyclophosphamide metabolism in the liver. However, Aldh1a1 deficiency did not affect hematopoiesis, HSC function, or the capacity to reconstitute irradiated recipients in young or old adult mice. Aldh1a1 deficiency also did not affect Aldefluor staining of hematopoietic cells. Finally, Aldh1a1 deficiency did not affect the function of stem cells from the adult central or peripheral nervous systems. Aldh1a1 is not a critical regulator of adult stem cell function or Aldefluor staining in mice.

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MLL fusion protein–driven AML is selectively inhibited by targeted disruption of the MLL-PAFc interaction

Blood ◽

10.1182/blood-2013-02-486977 ◽

2013 ◽

Vol 122 (11) ◽

pp. 1914-1922 ◽

Cited By ~ 10

Author(s):

Andrew G. Muntean ◽

Wei Chen ◽

Morgan Jones ◽

Eric M. Granowicz ◽

Ivan Maillard ◽

...

Keyword(s):

Stem Cell ◽

Fusion Protein ◽

Hematopoietic Stem Cell ◽

Epigenetic Regulation ◽

Cell Function ◽

Leukemic Cells ◽

Targeted Disruption ◽

Hematopoietic Stem ◽

Key Points

Key Points The PAFc subunit, Cdc73, is required for the proliferation and proper epigenetic regulation of proleukemic oncogenes in AML cells. Disrupting the MLL-PAFc interaction selectively inhibits the growth of MLL-associated leukemic cells without altering normal hematopoietic stem cell function.

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Ribosomes: An Exciting Avenue in Stem Cell Research

Stem Cells International ◽

10.1155/2020/8863539 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Zhenzhen Han ◽

Qi Zhang ◽

Yanbo Zhu ◽

Jingcheng Chen ◽

Wei Li

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Stem Cell ◽

Epigenetic Regulation ◽

Stem Cell Research ◽

Cellular Proliferation ◽

Cell Function ◽

Cellular Reprogramming ◽

Specific Gene ◽

Translation Efficiency

Stem cell research has focused on genomic studies. However, recent evidence has indicated the involvement of epigenetic regulation in determining the fate of stem cells. Ribosomes play a crucial role in epigenetic regulation, and thus, we focused on the role of ribosomes in stem cells. Majority of living organisms possess ribosomes that are involved in the translation of mRNA into proteins and promote cellular proliferation and differentiation. Ribosomes are stable molecular machines that play a role with changes in the levels of RNA during translation. Recent research suggests that specific ribosomes actively regulate gene expression in multiple cell types, such as stem cells. Stem cells have the potential for self-renewal and differentiation into multiple lineages and, thus, require high efficiency of translation. Ribosomes induce cellular transdifferentiation and reprogramming, and disrupted ribosome synthesis affects translation efficiency, thereby hindering stem cell function leading to cell death and differentiation. Stem cell function is regulated by ribosome-mediated control of stem cell-specific gene expression. In this review, we have presented a detailed discourse on the characteristics of ribosomes in stem cells. Understanding ribosome biology in stem cells will provide insights into the regulation of stem cell function and cellular reprogramming.

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