Inhibition of Sirt1 promotes neural progenitors toward motoneuron differentiation from human embryonic stem cells

Zhang, Yun; Wang, Jing; Chen, Guian; Fan, Dongsheng; Deng, Min

doi:10.1016/j.bbrc.2010.12.014

Cited by 53 publications

(37 citation statements)

References 26 publications

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“…Whether one or more lysine deacetylases (KDACs), including certain sirtuins (SIRTs), which can deacetylate H3K18 in vitro (Black et al 2008), are also involved remains to be determined. Interestingly, SIRT1 inhibition promotes differentiation (Pickard et al 2010;Zhang et al 2011), and its deletion induces inflammatory signaling in response to environmental stress (Schug et al 2010;Zhang et al 2010). This raises the possibility that H3K18 deacetylation could occur by sequestration of EP300/CREBBP and recruitment of these KATs to new but limited locations as well as active deacetylation by one or more KDACs to inhibit fibroblasts functions and antiviral responses and induce cell proliferation in the e1a-expressing cells.…”

Section: Discussionmentioning

confidence: 99%

Reorganization of the host epigenome by a viral oncogene

Ferrari

Su²,

Li³

et al. 2012

Genome Res.

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Adenovirus small e1a oncoprotein causes~70% reduction in cellular levels of histone H3 lysine 18 acetylation (H3K18ac). It is unclear, however, where this dramatic reduction occurs genome-wide. ChIP-sequencing revealed that by 24 h after expression, e1a erases 95% of H3K18ac peaks in normal, contact-inhibited fibroblasts and replaces them with one-third as many at new genomic locations. The H3K18ac peaks at promoters and intergenic regions of genes with fibroblast-related functions are eliminated after infection, and new H3K18ac peaks are established at promoters of highly induced genes that regulate cell cycling and at new putative enhancers. Strikingly, the regions bound by the retinoblastoma family of proteins in contact-inhibited fibroblasts gain new peaks of H3K18ac in the e1a-expressing cells, including 55% of RB1-bound loci. In contrast, over half of H3K9ac peaks are similarly distributed before and after infection, independently of RB1. The strategic redistribution of H3K18ac by e1a highlights the importance of this modification for transcriptional activation and cellular transformation as well as functional differences between the RB-family member proteins.

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Section: Discussionmentioning

confidence: 99%

Reorganization of the host epigenome by a viral oncogene

Ferrari

Su²,

Li³

et al. 2012

Genome Res.

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“…This agrees with a general role for SirT1 in the inhibition of differentiation. [24][25][26][27] Moreover, this might have important implications in cancer: first, because both SirT1 and Ezh2 protein levels are high in undifferentiated cells and decrease drastically upon differentiation and, second, because high levels of both factors correlate to cancer progression in a mouse model of prostate cancer. 28 The interaction of SirT1 with CH is more complex, and evidence suggests that it occurs at two different levels.…”

Section: Sirtuins and Chromatin Regulationmentioning

confidence: 99%

The Dual Role of Sirtuins in Cancer

Bosch-Presegué

Vaquero²

2011

Genes & Cancer

286

245

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Among the greatest challenges facing organisms is that of detecting and effectively responding to life-threatening environmental changes that are intimately associated with metabolic fluctuations and certain forms of stress. These conditions have been linked to the onset of many human pathologies, including cancer. Over the past decade, members of the Sir2 family, or sirtuins, have been described as major players in sensing and coordinating stress response. Evidence has imputed mammalian sirtuins in carcinogenesis, although the mechanisms involved seem to be more diverse and complex than previously anticipated. Some sirtuins, such as SirT2 and SirT6, seem to work as tumor suppressors, but others, such as SirT1, are apparently bifunctional: operating as both tumor suppressors and oncogenic factors depending on the context and the study conditions. The mechanisms underlying these apparently contradictory activities are not well understood, although recent findings suggest that they might actually be two sides of the same coin. In this review, the authors summarize current knowledge on the functional implications of sirtuins in cancer and discuss possible explanations for their functional duality.

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“…SIRT1 is highly expressed in metabolically active sites (e.g., in the ARC) and orchestrates key metabolic responses to nutrient alterations [33]. During development, SIRT1 and Hes1 form a complex that binds to and deacetylates histones at the Mash1 promoter [34], decreasing Mash1 expression. Similarly, SIRT1 and Hes1 may inhibit Ngn3 expression, and SIRT1 may inhibit Hes1.…”

Section: Appetite Regulationmentioning

confidence: 99%

Developmental Programming of Appetite/Satiety

Ross

Desai

2014

Ann Nutr Metab

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Obesity is often attributed to a Western lifestyle, a high-fat diet and decreased activity. While these factors certainly contribute to adult obesity, compelling data from our laboratory and others indicate that this explanation is oversimplified. Recent studies strongly argue that maternal/fetal under- or overnutrition predisposes the offspring to become hyperphagic and increases the risk of later obesity. Both infants small for gestational age (SGA) or infants born to obese mothers who consume a high-fat diet are at a markedly increased risk of adult obesity. Specific alterations in the fetal metabolic/energy environment directly influence the development of appetite regulatory pathways. Specifically, SGA infants demonstrate (1) impaired satiety and anorexigenic cell signaling, (2) enhanced cellular orexigenic responses, (3) programmed dysfunction of neuroprogenitor cell proliferation/differentiation, and (4) increased expression of appetite (NPY) versus satiety (POMC) neurons. In both hypothalamic tissue and ex vivo culture, SGA newborns exhibit increased levels of the nutrient sensor SIRT1, signifying reduced energy, whereas maternal high-fat-exposed newborns exhibit reduced levels of pAMPK, signifying energy excess. Via downstream regulation of bHLH neuroproliferation (Hes1) and neurodifferentiation factors (Mash1, Ngn3), neurogenesis is biased toward orexigenic and away from anorexigenic neurons, resulting in excess appetite, reduced satiety and development of obesity. Despite the developmental programming of appetite neurogenesis, the potential for neuronal remodeling raises the opportunity for novel interventions.

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Inhibition of Sirt1 promotes neural progenitors toward motoneuron differentiation from human embryonic stem cells

Cited by 53 publications

References 26 publications

Reorganization of the host epigenome by a viral oncogene

Reorganization of the host epigenome by a viral oncogene

The Dual Role of Sirtuins in Cancer

Developmental Programming of Appetite/Satiety

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