The role of α-ketoglutarate–dependent proteins in pluripotency acquisition and maintenance

Tran, Khoa; Dillingham, Caleb M.; Sridharan, Rupa

doi:10.1074/jbc.tm118.000831

Cited by 53 publications

(31 citation statements)

References 122 publications

(178 reference statements)

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“…In conjunction with Tet enzymes, enzymes that mediated histone demethylation, JMJD2 (Jumanji domain‐containing protein 2), and JARID1 (Jumonji, AT rich interactive domain 1) families of the N ε ‐trimethyl‐lysine demethylases are also Fe (II) and αKG dependent. [ 74–76 ] These demethylases target histone H3K9Me3 marks that are a characteristic of heterochromatin, and loss of these marks has been associated with Hutchinson–Gilford Progeria Syndrome, a disease of accelerated aging. [ 77,78 ] Therefore control of levels of histone methylation associated with the H3K9Me3 is expected to have profound impacts on aging.…”

Section: Application Of Metabolomics For Biomarker Discovery In Agingmentioning

confidence: 99%

The Aging Metabolome—Biomarkers to Hub Metabolites

Sharma

Ramanathan

2020

Proteomics

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Aging biology is intimately associated with dysregulated metabolism, which is one of the hallmarks of aging. Aging‐related pathways such as mTOR and AMPK, which are major targets of anti‐aging interventions including rapamcyin, metformin, and exercise, either directly regulate or intersect with metabolic pathways. In this review, numerous candidate bio‐markers of aging that have emerged using metabolomics are outlined. Metabolomics studies also reveal that not all metabolites are created equally. A set of core “hub” metabolites are emerging as central mediators of aging. The hub metabolites reviewed here are nicotinamide adenine dinucleotide, reduced nicotinamide dinucleotide phosphate, α‐ketoglutarate, and β‐hydroxybutyrate. These “hub” metabolites have signaling and epigenetic roles along with their canonical roles as co‐factors or intermediates of carbon metabolism. Together these hub metabolites suggest a central role of the TCA cycle in signaling and metabolic dysregulation associated with aging.

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Section: Application Of Metabolomics For Biomarker Discovery In Agingmentioning

confidence: 99%

The Aging Metabolome—Biomarkers to Hub Metabolites

Sharma

Ramanathan

2020

Proteomics

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“…1) (Apostolou and Hochedlinger, 2013;Gurdon and Melton, 2008;Hanna et al, 2010;Stadtfeld and Hochedlinger, 2010;Yamanaka and Blau, 2010). Given the therapeutic potential of the reprogramming approach, subsequent studies focused on improving the efficiency of TF-mediated reprogramming (Bar-Nur et al, 2014;Di Stefano et al, 2014;Esteban et al, 2010;Onder et al, 2012;Tran et al, 2019a;Vidal et al, 2014;Yamanaka, 2007). These and other studies demonstrated that, although it is possible to modulate the identity of certain cell types, many safeguarding mechanisms exist to prohibit reprogramming from occurring naturally.…”

Section: Introductionmentioning

confidence: 99%

Reprogramming: identifying the mechanisms that safeguard cell identity

2019

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Development and homeostasis rely upon concerted regulatory pathways to establish the specialized cell types needed for tissue function. Once a cell type is specified, the processes that restrict and maintain cell fate are equally important in ensuring tissue integrity. Over the past decade, several approaches to experimentally reprogram cell fate have emerged. Importantly, efforts to improve and understand these approaches have uncovered novel molecular determinants that reinforce lineage commitment and help resist cell fate changes. In this Review, we summarize recent studies that have provided insights into the various chromatin factors, post-transcriptional processes and features of genomic organization that safeguard cell identity in the context of reprogramming to pluripotency. We also highlight how these factors function in other experimental, physiological and pathological cell fate transitions, including direct lineage conversion, pluripotencyto-totipotency reversion and cancer.

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“…AA in recent years has been recognized as a potent modulator of the activity of chromatinmodifying enzymes (Cimmino et al, 2018;Monfort and Wutz, 2013), in particular of histone and DNA demethylases. In general, activation of AA-dependent enzymes is associated with successful nuclear reprogramming and iPSC formation (Chen et al, 2013b;Esteban et al, 2010;Tran et al, 2019). To explain our observation of impaired reprogramming in presence of AA, we speculated that EHMT1/2 might be required to balance the activities of specific enzymes that are stimulated by AA.…”

Section: Ehmt1/2 Activity Balances Aa-stimulated H3k9 Demethylases Dumentioning

confidence: 85%

Context-dependent requirement of H3K9 methyltransferase activity during cellular reprogramming to iPSCs

Vidal

Polyzos

Valencia

et al. 2019

Preprint

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Methylation of histone 3 at lysine 9 (H3K9) is widely regarded as a major roadblock for cellular reprogramming and interference with associated methyltransferases such as EHMT1 and EHMT2 (also known as GLP and G9A, respectively) increases the efficiencies at which induced pluripotent stem cells (iPSCs) can be derived. Activation of histone and DNA demethylases by ascorbic acid (AA) has become a common approach to facilitate the extensive epigenetic remodeling required for iPSC formation, but possible functional interactions between the H3K9 methylation machinery and AA-stimulated enzymes remain insufficiently explored. Here we show that reduction of EHMT1/2 activity counteracts iPSC formation in an optimized reprogramming system in the presence of AA. Mechanistically, EHMT1/2 activity under these conditions is required for efficient downregulation of somatic genes and transition into an epithelial state. Of note, transient inhibition of EHMT1/2 during reprogramming yields iPSCs that fail to efficiently give rise to viable mice, suggesting persistent molecular defects in these cells.Genetic interference with the H3K9 demethylase KDM3B ameliorated the adverse effect of EHMT1/2 inhibition on iPSC formation. Together, our observations document novel functions of H3K9 methyltransferases during iPSC formation and suggest that the balancing of AAstimulated enzymes by EHMT1/2 supports efficient and error-free iPSC reprogramming to pluripotency.3

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The role of α-ketoglutarate–dependent proteins in pluripotency acquisition and maintenance

Cited by 53 publications

References 122 publications

The Aging Metabolome—Biomarkers to Hub Metabolites

The Aging Metabolome—Biomarkers to Hub Metabolites

Reprogramming: identifying the mechanisms that safeguard cell identity

Context-dependent requirement of H3K9 methyltransferase activity during cellular reprogramming to iPSCs

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