TAF12 Recruits Gadd45a and the Nucleotide Excision Repair Complex to the Promoter of rRNA Genes Leading to Active DNA Demethylation

Schmitz, Kerstin Maike; Schmitt, Nina; Hoffmann-Rohrer, Urs; Schäfer, Andrea; Grummt, Ingrid; Mayer, Christine

doi:10.1016/j.molcel.2009.01.015

Cited by 180 publications

(140 citation statements)

References 40 publications

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“…All together, the extent to which the observed changes in DNA methylation in this study affect gene expression over time, in a subset of individuals at risk or during certain specific metabolic challenges remain to be determined. The induction of DNA methylation changes after 5 days of HFO supports the growing awareness of DNA methylation as a dynamic signal that is possibly relevant to shortterm day-to-day metabolic adaptations, including acute exercise [26,29,30]. However, our finding of a slow reversibility rate indicates the demethylation process may be somewhat impeded compared with the induction of methylation changes by diet, which could have implications for the preservation or build-up of CpG methylation over time.…”

Section: Discussionsupporting

confidence: 68%

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

et al. 2012

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Aims/hypothesis Energy-dense diets that are high in fat are associated with a risk of metabolic diseases. The underlying molecular mechanisms could involve epigenetics, as recent data show altered DNA methylation of putative type 2 diabetes candidate genes in response to high-fat diets. We examined the effect of a short-term high-fat overfeeding (HFO) diet on genome-wide DNA methylation patterns in human skeletal muscle. Methods Skeletal muscle biopsies were obtained from 21 healthy young men after ingestion of a short-term HFO diet and a control diet, in a randomised crossover setting. DNA methylation was measured in 27,578 CpG sites/14,475 genes using Illumina's Infinium Bead Array. Candidate gene expression was determined by quantitative real-time PCR. Results HFO introduced widespread DNA methylation changes affecting 6,508 genes (45%), with a maximum methylation change of 13.0 percentage points. The HFO-induced methylation changes were only partly and non-significantly reversed after 6-8 weeks. Alterations in DNA methylation levels primarily affected genes involved in inflammation, the reproductive system and cancer. Few gene expression changes were observed and these had poor correlation to DNA methylation. Conclusions/interpretation The genome-wide DNA methylation changes induced by the short-term HFO diet could have implications for our understanding of transient epigenetic regulation in humans and its contribution to the development of metabolic diseases. The slow reversibility suggests a methylation build-up with HFO, which over time may influence gene expression levels.

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Section: Discussionsupporting

confidence: 68%

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

et al. 2012

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“…Additionally, small molecule inhibitors of BER inhibit the progression of DNA demethylation, further supporting the mechanistic link between those two processes [11]. While some of the previous studies have suggested a possible link between the nucleotide excision repair (NER) pathway and active DNA demethylation [26,27], it is noteworthy that no evidence has been found for NER involvement either in the germline or in zygotic DNA demethylation [11]. The cumulative evidence thus points towards at least some level of mechanistic conservation between DNA demethylation processes in mammals and plants.…”

Section: Role Of Base Excision Dna Repair In Active Dna Demethylationmentioning

confidence: 82%

Epigenetic reprogramming in the germline: towards the ground state of the epigenome

Hájková

2011

Phil. Trans. R. Soc. B

105

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Epigenetic reprogramming in the germline provides a developmental model to study the erasure of epigenetic memory as it occurs naturally in vivo in the course of normal embryonic development. Our data show that germline reprogramming comprises both active DNA demethylation and extensive chromatin remodelling that are mechanistically linked through the activation of the base excision DNA repair pathway involved in the DNA demethylation process. The observed molecular hallmarks of the germline reprogramming exhibit intriguing similarities to other dedifferentiation or regeneration systems, pointing towards the existence of unifying molecular pathways underlying cell fate reversal. Elucidation of molecular processes involved in the resetting of epigenetic information in vivo will thus add to our ability to manipulate cell fate and to restore pluripotency in in vitro settings.

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“…Knocking down the RPL11 gene in zebrafish was shown to activate the p53 pathway (26). TAF2 is a transcription factor that has been implicated in core promoter selectivity of RNA polymerase II (27). DefA4 is a gene involved in neutrophil function (28) whose expression was increased by DFMO (Fig.…”

Section: Dfmo Modulates Gene Expression In Barrett's Mucosamentioning

confidence: 99%

Evaluation of Difluoromethylornithine for the Chemoprevention of Barrett's Esophagus and Mucosal Dysplasia

Sinicrope

Broaddus

Joshi

et al. 2011

Cancer Prevention Research

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Patients with Barrett's esophagus (BE) and dysplasia are candidates for chemopreventive strategies to reduce cancer risk. We determined the effects of difluoromethylornithine (DMFO) on mucosal polyamines, gene expression, and histopathology in BE. Ten patients with BE and low-grade dysplasia participated in a single-arm study of DFMO (0.5 g/m 2 /d) given continuously for 6 months. Esophagoscopy with biopsies was conducted at baseline, 3, 6, and 12 months. Dysplasia was graded by a gastrointestinal pathologist. Audiology was assessed (at baseline and at 6 months). Mucosal polyamines were measured by high-performance liquid chromatography. Microarray-based gene expression was analyzed using a cDNA two-color chip. DFMO suppressed levels of the polyamines putrescine (P ¼ 0.02) and spermidine (P ¼ 0.02) and the spermidine/spermine ratio (P < 0.01) in dysplastic BE (6 months vs. baseline) that persisted at 6 months following drug cessation. Among the top 25 modulated genes, we found those regulating p53-mediated cell signaling (RPL11), cell-cycle regulation (cyclin E2), and cell adhesion and invasion (Plexin1). DFMO downregulated Kr€ uppellike factor 5 (KLF5), a transcription factor promoting cell proliferation, and suppressed RFC5 whose protein interacts with proliferating cell nuclear antigen. Histopathology showed regression of dysplasia (n ¼ 1), stable disease (n ¼ 8), and progression to high-grade dysplasia (n ¼ 1). Polyamines were suppressed in the responder to a greater extent than in stable cases. DFMO was well tolerated, and one patient had subclinical, unilateral ototoxicity. DFMO suppressed mucosal polyamines and modulated genes that may be mechanistically related to its chemopreventive effect. Further study of DFMO for the chemoprevention of esophageal cancer in BE patients is warranted.

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TAF12 Recruits Gadd45a and the Nucleotide Excision Repair Complex to the Promoter of rRNA Genes Leading to Active DNA Demethylation

Cited by 180 publications

References 40 publications

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

Effects of short-term high-fat overfeeding on genome-wide DNA methylation in the skeletal muscle of healthy young men

Epigenetic reprogramming in the germline: towards the ground state of the epigenome

Evaluation of Difluoromethylornithine for the Chemoprevention of Barrett's Esophagus and Mucosal Dysplasia

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