Nutrient-Driven O-GlcNAcylation at Promoters Impacts Genome-Wide RNA Pol II Distribution

Krause, Michael; Love, Dona C.; Ghosh, Salil; Wang, Peng; Yun, Sijung; Fukushige, Tetsunari; Hanover, John A.

doi:10.3389/fendo.2018.00521

Cited by 13 publications

(8 citation statements)

References 75 publications

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“…Glycosylation of RNA-Pol II CTD has been shown to regulate pre-initiation complex formation using in vitro assays and O-GlcNAc mark is found on the promoters in human cell lines as reported here and shown by others 12, 13, 44. In addition, O-GlcNAc is enriched on the promoters in Caenorhabditis elegans , but the modification is not responsive to nutrients 63. Perturbation of OGT activity in specific cell or organ type has prominent effects on transcription and overall physiology of the animal in mouse studies 62, 64, however, given the high number of OGT-targets, it is not possible to attribute these effects directly to transcription.…”

Section: Discussionsupporting

confidence: 75%

High OGT activity is essential for MYC-driven proliferation of prostate cancer cells

et al. 2019

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O-GlcNAc transferase (OGT) is overexpressed in aggressive prostate cancer. OGT modifies intra-cellular proteins via single sugar conjugation (O-GlcNAcylation) to alter their activity. We recently discovered the first fast-acting OGT inhibitor OSMI-2. Here, we probe the stability and function of the chromatin O-GlcNAc and identify transcription factors that coordinate with OGT to promote proliferation of prostate cancer cells. Methods : Chromatin immunoprecipitation (ChIP) coupled to sequencing (seq), formaldehyde-assisted isolation of regulatory elements, RNA-seq and reverse-phase protein arrays (RPPA) were used to study the importance of OGT for chromatin structure and transcription. Mass spectrometry, western blot, RT-qPCR, cell cycle analysis and viability assays were used to establish the role of OGT for MYC-related processes. Prostate cancer patient data profiled for both mRNA and protein levels were used to validate findings. Results : We show for the first time that OGT inhibition leads to a rapid loss of O-GlcNAc chromatin mark. O-GlcNAc ChIP-seq regions overlap with super-enhancers (SE) and MYC binding sites. OGT inhibition leads to down-regulation of SE-dependent genes. We establish the first O-GlcNAc chromatin consensus motif, which we use as a bait for mass spectrometry. By combining the proteomic data from oligonucleotide enrichment with O-GlcNAc and MYC ChIP-mass spectrometry, we identify host cell factor 1 (HCF-1) as an interaction partner of MYC. Inhibition of OGT disrupts this interaction and compromises MYC's ability to confer androgen-independent proliferation to prostate cancer cells. We show that OGT is required for MYC-mediated stabilization of mitotic proteins, including Cyclin B1, and/or the increased translation of their coding transcripts. This implies that increased expression of mRNA is not always required to achieve increased protein expression and confer aggressive phenotype. Indeed, high expression of Cyclin B1 protein has strong predictive value in prostate cancer patients (p=0.000014) while mRNA does not. Conclusions : OGT promotes SE-dependent gene expression. OGT activity is required for the interaction between MYC and HCF-1 and expression of MYC-regulated mitotic proteins. These features render OGT essential for the androgen-independent, MYC-driven proliferation of prostate cancer cells. Androgen-independency is the major mechanism of prostate cancer progression, and our study identifies OGT as an essential mediator in this process.

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Section: Discussionsupporting

confidence: 75%

High OGT activity is essential for MYC-driven proliferation of prostate cancer cells

et al. 2019

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“…3). O-GlcNAcylation is thought to be involved in key cellular processes such as gene regulation and expression [22][23][24], metabolic activity [25], and cellcycle regulation [26]. Changes in O-GlcNAc homoeostasis have been linked to severe developmental problems and neurodegenerative diseases [27][28][29][30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

An intellectual disability syndrome with single-nucleotide variants in O-GlcNAc transferase

et al. 2020

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Intellectual disability (ID) is a neurodevelopmental condition that affects~1% of the world population. In total 5−10% of ID cases are due to variants in genes located on the X chromosome. Recently, variants in OGT have been shown to co-segregate with X-linked intellectual disability (XLID) in multiple families. OGT encodes O-GlcNAc transferase (OGT), an essential enzyme that catalyses O-linked glycosylation with β-N-acetylglucosamine (O-GlcNAc) on serine/threonine residues of thousands of nuclear and cytosolic proteins. In this review, we compile the work from the last few years that clearly delineates a new syndromic form of ID, which we propose to classify as a novel Congenital Disorder of Glycosylation (OGT-CDG). We discuss potential hypotheses for the underpinning molecular mechanism(s) that provide impetus for future research studies geared towards informed interventions.

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“…We identified enzymes and mitochondrial proteins in which a link between O- GlcNAcylation and impaired catalytic activity was previously described in diabetes ( 17 , 39 ). The second was transcriptional regulation, in part, through O- GlcNAcylation of transcriptional regulators ( 46 , 47 ). It should be noted that additional mechanisms likely exist, such as an emerging role of metabolic regulation of epigenetics and its impact on gene expression ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

Wende

Schell

et al. 2020

Diabetes

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Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear whether these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy, we generated transgenic mice with inducible cardiomyocyte-specific expression of the GLUT4. We examined mice rendered hyperglycemic following lowdose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in nondiabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucosedependent transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct O-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest that reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.

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Nutrient-Driven O-GlcNAcylation at Promoters Impacts Genome-Wide RNA Pol II Distribution

Cited by 13 publications

References 75 publications

High OGT activity is essential for MYC-driven proliferation of prostate cancer cells

High OGT activity is essential for MYC-driven proliferation of prostate cancer cells

An intellectual disability syndrome with single-nucleotide variants in O-GlcNAc transferase

Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

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