A Novel Transcription Mechanism Activated by Ethanol

Lin, Xinghua; Hong, Yun–Chul; Zhang, Hongfeng; Zhou, Lichun; Guo, ZhongMao

doi:10.1074/jbc.m113.466565

Cited by 25 publications

(10 citation statements)

References 44 publications

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“…These data suggest that an intermittent (ethanol self-administration, twice a week), or a long-term ethanol exposure (in the liquid diet), cause an increase of the xCT in the whole brain. Interestingly, these results are in agreement with data obtained from Lin et al ( 2013 ), who reported that ethanol treatment up-regulates xCT expression in vitro (Lin et al, 2013 ).…”

Section: Discussionsupporting

confidence: 93%

“…Recently, Pochareddy and Edenberg ( 2012 ) demonstrated that long-term ethanol exposure in vitro results in altered expression of roughly thousand genes in human hepatoma cells (HepG2) among which the Slc7a11 gene, has been shown to be expressed at higher levels (1.54-fold), whereas other authors have shown that ethanol, dose-dependently, increases the xCT exchanger expression in mouse hepatic stellate cells (Lin et al, 2013 ). Notably, the main function of the xCT antiporter is to maintain the intracellular level of glutathione and protect cells from oxidative damage (Bannai, 1986 ; Pochareddy and Edenberg, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

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Change of cystine/glutamate antiporter expression in ethanol-dependent rats

Peana¹,

Muggironi²,

Bennardini³

2014

Front. Neurosci.

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Background: Some drugs of abuse down regulate the expression of cystine/glutamate (xCT) antiporter in the nucleus accumbens (Acb) after extinction or withdrawal. The altered level of xCT exchanger in Acb, a structure involved in ethanol reinforcement, may contribute to the pathological glutamatergic signaling, linked to addiction. We hypothesized that the expression of xCT may be changed in Acb and whole brain also in non-dependent (occasional drinkers), ethanol-dependent rats, as well as, during ethanol withdrawal.Methods: Wistar rats were made ethanol-dependent by chronic exposure to an alcoholic milk beverage (from 2.4 to 7.2% v/v ethanol). Ethanol non-dependent rats were exposed to a similar, but non-alcoholic liquid diet and self-administered ethanol (10%) twice a week. Withdrawal in ethanol-dependent rats was studied at 12 h after the last ethanol-enriched diet exposure. Immediately after the measurement of somatic signs of withdrawal, Western blot analysis with a polyclonal antibody against xCT was carried out in a naïve control group, non-dependent and ethanol-dependent rats as well as withdrawal rats, in order to study the level of xCT expression in Acb and whole brain.Results: Non-dependent rats self-administered an average dose of 1.21 ± 0.02 g/kg per session (30 min). Daily ethanol consumption during chronic exposure to the alcoholic beverage ranged from 6.30 ± 0.16 to 13.99 ± 0.66 g/kg. Ethanol dependent rats after suspension of the ethanol-enriched diet have shown significant somatic signs of withdrawal. Western blotting analysis of Acb lysates revealed that xCT was over expressed in ethanol-dependent rats whereas in whole brain preparations xCT was over expressed in both non-dependent and ethanol-dependent rats compared to control group. On the contrary, xCT expression during withdrawal was down regulated in Acb and restored to control level in whole brain preparations.Conclusions: The changes of xCT expression in both Acb and whole brain following ethanol dependence and withdrawal indicate that xCT might represent a novel therapeutic target for the treatment of ethanol addiction.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Change of cystine/glutamate antiporter expression in ethanol-dependent rats

Peana¹,

Muggironi²,

Bennardini³

2014

Front. Neurosci.

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“…Finally, we investigated the mechanism of xCT activation during liver repopulation. Several transcription factors have been shown to regulate Slc7a11 expression in different contexts: nuclear factor E2-related factor 2 (NRF2) activates xCT during redox stress (48), activating transcription factor 4 (ATF4) upregulates xCT under ER stress (49), octamer-binding transcription factor (OCT1) disinhibits Slc7a11 following ethanol exposure (50), and p53 inhibits xCT under normal tumor suppression conditions (51). Additionally, ATF4 is suggested to regulate the basal levels of Slc7a11 expression (49).…”

Section: Resultsmentioning

confidence: 99%

TRAP-seq identifies cystine/glutamate antiporter as a driver of recovery from liver injury

Wang¹,

Wangensteen²,

Wang³

et al. 2018

Journal of Clinical Investigation

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Understanding the molecular basis of the regenerative response following hepatic injury holds promise for improved treatment of liver diseases. Here, we report an innovative method to profile gene expression specifically in the hepatocytes that regenerate the liver following toxic injury. We used the Fah-/- mouse, a model of hereditary tyrosinemia, which conditionally undergoes severe liver injury unless fumarylacetoacetate hydrolase (FAH) expression is reconstituted ectopically. We used translating ribosome affinity purification followed by high-throughput RNA sequencing (TRAP-seq) to isolate mRNAs specific to repopulating hepatocytes. We uncovered upstream regulators and important signaling pathways that are highly enriched in genes changed in regenerating hepatocytes. Specifically, we found that glutathione metabolism, particularly the gene Slc7a11 encoding the cystine/glutamate antiporter (xCT), is massively upregulated during liver regeneration. Furthermore, we show that Slc7a11 overexpression in hepatocytes enhances, and its suppression inhibits, repopulation following toxic injury. TRAP-seq allows cell type-specific expression profiling in repopulating hepatocytes and identified xCT, a factor that supports antioxidant responses during liver regeneration. xCT has potential as a therapeutic target for enhancing liver regeneration in response to liver injury.

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“…Since false positive bQTLs would agree only ~50% of the time, this suggests false discovery rates of between 7.8–13.8% for these bQTLs (though these estimates, which conservatively assume that the previously reported H3K4me3 QTLs have no false positives and that the true overlaps always agree in direction, cannot be extrapolated to all bQTLs) (see Supplemental Experimental Procedures). The one TF with lower (85.9%) agreement, Pou2f1, has been shown to sometimes act as a repressor (Lin et al, 2013), which may explain this difference. We observed almost identical concordance among bQTLs occurring outside of their TF’s consensus motifs (Figure S3C), suggesting that these bQTLs are not enriched for false positives.…”

Section: Resultsmentioning

confidence: 99%

Pooled ChIP-Seq Links Variation in Transcription Factor Binding to Complex Disease Risk

Tehranchi

Myrthil

Martin

et al. 2016

Cell

113

143

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Summary Cis -regulatory elements such as transcription factor (TF) binding sites can be identified genome-wide, but it remains far more challenging to pinpoint genetic variants affecting TF binding. Here we introduce a pooling-based approach to mapping quantitative trait loci (QTLs) for molecular-level traits. Applying this to five TFs and a histone modification, we mapped thousands of cis-acting QTLs, with over 25-fold lower cost compared to standard QTL mapping. We found that single genetic variants frequently affect binding of multiple TFs, and that CTCF can recruit all five TFs to its binding sites. These QTLs often affect local chromatin and transcription, but can also influence long-range chromosomal contacts, demonstrating a role for natural genetic variation in chromosomal architecture. Thousands of these QTLs have been implicated in genome-wide association studies, providing candidate molecular mechanisms for many disease risk loci, and suggesting that TF binding variation may underlie a large fraction of human phenotypic variation.

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A Novel Transcription Mechanism Activated by Ethanol

Cited by 25 publications

References 44 publications

Change of cystine/glutamate antiporter expression in ethanol-dependent rats

Change of cystine/glutamate antiporter expression in ethanol-dependent rats

TRAP-seq identifies cystine/glutamate antiporter as a driver of recovery from liver injury

Pooled ChIP-Seq Links Variation in Transcription Factor Binding to Complex Disease Risk

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