Gatekeepers of chromatin: Small metabolites elicit big changes in gene expression

Kaochar, Salma; Tu, Benjamin P.

doi:10.1016/j.tibs.2012.07.008

Cited by 42 publications

(36 citation statements)

References 80 publications

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“…Owing to increased lipid load and lack of an adaptive increase in mitochondrial oxidation, excess fatty acids in the fetus might not be completely oxidized, creating a backup of incomplete acylcoenzyme A species that can impair cell metabolism via increased cell stress, increased inflammation and decreased mitochondrial function and gene expression 84,85 . In this context, excess free fatty acids combined with reduced mitochondrial metabolism could limit mitochondrial biogenesis.…”

Section: Intrauterine Clues For Nafld Riskmentioning

confidence: 99%

Developmental origins of NAFLD: a womb with a clue

Wesolowski

Kasmi

Jonscher

et al. 2016

Nat Rev Gastroenterol Hepatol

179

167

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Changes in the maternal environment leading to an altered intrauterine milieu can result in subtle insults to the fetus, promoting increased lifetime disease risk and/or disease acceleration in childhood and later in life. Particularly worrisome is that the prevalence of NAFLD is rapidly increasing among children and adults, and is being diagnosed at increasingly younger ages, pointing towards an early-life origin. A wealth of evidence, in humans and non-human primates, suggests that maternal nutrition affects the placenta and fetal tissues, leading to persistent changes in hepatic metabolism, mitochondrial function, the intestinal microbiota, liver macrophage activation and susceptibility to NASH postnatally. Deleterious exposures in utero include fetal hypoxia, increased nutrient supply, inflammation and altered gut microbiota that might produce metabolic clues, including fatty acids, metabolites, endotoxins, bile acids and cytokines, which prime the infant liver for NAFLD in a persistent manner and increase susceptibility to NASH. Mechanistic links to early disease pathways might involve shifts in lipid metabolism, mitochondrial dysfunction, pioneering gut microorganisms, macrophage programming and epigenetic changes that alter the liver microenvironment, favouring liver injury. In this Review, we discuss how maternal, fetal, neonatal and infant exposures provide developmental clues and mechanisms to help explain NAFLD acceleration and increased disease prevalence. Mechanisms identified in clinical and preclinical models suggest important opportunities for prevention and intervention that could slow down the growing epidemic of NAFLD in the next generation.NAFLD is a general term used to describe a broad spectrum of liver abnormalities, ranging from simple, uncomplicated hepatic steatosis to NASH, accompanied by different degrees of Correspondence to J.E.F. jed.friedman@ucdenver.edu. Author contributionsAll authors researched data for the article, provided a substantial contribution to discussion of content, wrote the article, and reviewed and edited the manuscript before submission. Competing interests statementThe authors declare no competing interests. HHS Public AccessAuthor manuscript Nat Rev Gastroenterol Hepatol. Author manuscript; available in PMC 2017 December 12. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript inflammation and fibrosis. NAFLD is increasing in prevalence, especially in adolescents 1 , despite the levellingoff of the obesity epidemic from 2003-2004 to 2013-2014 in children and adolescents aged 2-19 years (REF.2). The most common chronic liver disease worldwide, NAFLD increases the risk of cardiovascular events eightfold and type 2 diabetes mellitus (T2DM) threefold 3 , and is a strong risk factor for hepatocellular carcinoma (HCC) 4 . At the time of paediatric NAFLD diagnosis, 25-50% of children have NASH and 10-25% have advanced fibrosis 5 . For many decades, it was thought that NAFLD was predominantly driven by obesity in the setting of genetic suscep...

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Section: Intrauterine Clues For Nafld Riskmentioning

confidence: 99%

Developmental origins of NAFLD: a womb with a clue

Wesolowski

Kasmi

Jonscher

et al. 2016

Nat Rev Gastroenterol Hepatol

179

167

View full text Add to dashboard Cite

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“…Acetyl-CoA is a major acetyl donor in the acetylation of histones and non-histone proteins (Kaochar and Tu, 2012). Considering acetyl-CoA accumulation in cytoplasm ( Figure 1H), we spiked the TPO-treated CD110+ cells with 13 C-lysine and immunoprecipitated acetylated peptides from cytoplasmic extracts to identify candidates containing 13 C-acetyllysine.…”

Section: Lysine Catabolism Is Indispensable For Liver Colonization Bymentioning

confidence: 99%

TPO-Induced Metabolic Reprogramming Drives Liver Metastasis of Colorectal Cancer CD110+ Tumor-Initiating Cells

et al. 2015

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Liver metastasis is a leading cause of death in patients with colorectal cancer. We previously found that colorectal cancer tumor-initiating cells (TICs) expressing CD110, the thrombopoietin (TPO)-binding receptor, mediate liver metastasis. Here, we show that TPO promotes metastasis of CD110+ TICs to the liver by activating lysine degradation. Lysine catabolism generates acetyl-CoA, which is used in p300-dependent LRP6 acetylation. This triggers tyrosine phosphorylation of LRP6, ultimately activating Wnt signaling to promote self-renewal of CD110+ TICs. Lysine catabolism also generates glutamate, which modulates the redox status of CD110+ TICs to promote liver colonization and drug resistance. Mechanistically, TPO-mediated induction of c-myc orchestrates recruitment of chromatin modifiers to regulate metabolic gene expression. Our findings, therefore, establish TPO as a component of the physiological environment critical for metastasis of colorectal cancer to the liver.

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“…Here we discuss emerging evidence that particular histone modifications depend on metabolites, either as cofactors or substrates, providing mechanisms by which fluctuating levels of specific metabolites directly and rapidly influence gene activity. As such, these metabolites may be viewed as ‘gatekeepers of chromatin’, enabling modulation of the chromatin landscape in response to key nutritional cues [11]. …”

Section: Rapid Changes In Gene Expression In Response To Nutrient Shiftsmentioning

confidence: 99%

Dietary control of chromatin

Huang

Cai

2015

Current Opinion in Cell Biology

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Organisms must be able to rapidly alter gene expression in response to changes in their nutrient environment. This review summarizes evidence that epigenetic modifications of chromatin depend on particular metabolites of intermediary metabolism, enabling the facile regulation of gene expression in tune with metabolic state. Nutritional or dietary control of chromatin is an often-overlooked, yet fundamental regulatory mechanism directly linked to human physiology. Nutrient-sensitive epigenetic marks are dynamic, suggesting rapid turnover, and may have functions beyond the regulation of gene transcription, including pH regulation and as carbon sources in cancer cells.

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Gatekeepers of chromatin: Small metabolites elicit big changes in gene expression

Cited by 42 publications

References 80 publications

Developmental origins of NAFLD: a womb with a clue

Developmental origins of NAFLD: a womb with a clue

TPO-Induced Metabolic Reprogramming Drives Liver Metastasis of Colorectal Cancer CD110+ Tumor-Initiating Cells

Dietary control of chromatin

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