Relationship between methylome and transcriptome in patients with nonalcoholic fatty liver disease.
TL;DR: Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD.
About: This article is published in Gastroenterology.The article was published on 2013-11-01 and is currently open access. It has received 300 citations till now. The article focuses on the topics: Nonalcoholic fatty liver disease & Fatty liver.
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TL;DR: Experts reached consensus that NAFLD does not reflect current knowledge and metabolic (dysfunction) associated fatty liver disease "MAFLD" was suggested as a more appropriate overarching term and opens the door for efforts from the research community to update the nomenclature and sub-phenotype the disease in order to accelerate the translational path to new treatments.
1,544 citations
TL;DR: Gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre‐/probiotics therapies, and identifies Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis.
896 citations
Cites background from "Relationship between methylome and ..."
...Several other factors that influence the course of the disease have been identified, such as epigenetics,((4)) hormonal status,((5)) or nutrition....
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TL;DR: The status of research into important genetic and epigenetic modifiers of NAFLD progression are discussed and the potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored.
582 citations
Washington University in St. Louis1, The Chinese University of Hong Kong2, Boston Children's Hospital3, Newcastle University4, National Scientific and Technical Research Council5, University of California, San Francisco6, University of Turin7, University of California, San Diego8, Saint Louis University9, Northwestern University10
TL;DR: No effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery, however, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation.
Abstract: Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring.
546 citations
TL;DR: The authors comprehensively discuss the key factors that trigger hepatic inflammation, as well as the pathways involved in inflammation resolution, which help to design targeted therapies able to halt or reverse disease progression in NASH.
Abstract: Nonalcoholic steatohepatitis (NASH) is considered the progressive form of nonalcoholic fatty liver disease (NAFLD) and is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis. A central issue in this field relates to the identification of those factors that trigger inflammation, thus fuelling the transition from nonalcoholic fatty liver to NASH. These triggers of liver inflammation might have their origins outside the liver (such as in adipose tissue or the gut) as well as inside the organ (for instance, lipotoxicity, innate immune responses, cell death pathways, mitochondrial dysfunction and endoplasmic reticulum stress), both of which contribute to NASH development. In this Review, we summarize the currently available information on the key upstream triggers of inflammation in NASH. We further delineate the mechanisms by which liver inflammation is resolved and the implications of a defective pro-resolution process. A better knowledge of these mechanisms should help to design targeted therapies able to halt or reverse disease progression.
482 citations
References
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Harvard University1, Brigham and Women's Hospital2, University of Wisconsin-Madison3, University of California, Berkeley4, Technical University of Denmark5, Icahn School of Medicine at Mount Sinai6, Vienna University of Technology7, University of Erlangen-Nuremberg8, German Cancer Research Center9, University of Milan10, Johns Hopkins University11, University of Washington12, Scripps Research Institute13, Walter and Eliza Hall Institute of Medical Research14, University of Iowa15
TL;DR: Details of the aims and methods of Bioconductor, the collaborative creation of extensible software for computational biology and bioinformatics, and current challenges are described.
Abstract: The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. The goals of the project include: fostering collaborative development and widespread use of innovative software, reducing barriers to entry into interdisciplinary scientific research, and promoting the achievement of remote reproducibility of research results. We describe details of our aims and methods, identify current challenges, compare Bioconductor to other open bioinformatics projects, and provide working examples.
12,142 citations
"Relationship between methylome and ..." refers methods in this paper
...Data analyses were performed using R/Bioconductor statistical packages.(11)...
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TL;DR: This is a practice guideline for clinicians rather than a review article and interested readers can refer to several comprehensive reviews published recently.
3,212 citations
"Relationship between methylome and ..." refers background or methods in this paper
...Our results were generated from percutaneous liver biopsy samples of wellcharacterized patients with NAFLD, one of the most common types of chronic liver disease in adults.(1) Liver histology, the current gold standard diagnostic test,(1) was used to segregate these subjects into 2 groups that are predicted to have extremely different liver outcomes at 10 years, based on differences in the severity of liver fibrosis at the time of tissue acquisition....
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...It is now the most common cause of chronic liver disease in the United States and Western Europe.(1) NAFLD encompasses a spectrum of liver pathology that is generally characterized by excessive accumulation of fat in hepatocytes (ie, steatosis)....
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...Currently, liver biopsy is the only way to reliably stage the severity of liver fibrosis and thereby distinguish individuals with mild NAFLD from those with advanced NAFLD before overt clinical sequelae of liver damage emerge.(1) This limits population-based screening, delaying diagnosis of individuals with NAFLD who are at high risk for eventual liver-related morbidity and mortality....
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...It is now the most common cause of chronic liver disease in the United States and Western Europe.1 NAFLD encompasses a spectrum of liver pathology that is generally characterized by excessive accumulation of fat in hepatocytes (ie, steatosis)....
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University of Washington1, Duke University2, Fred Hutchinson Cancer Research Center3, University of Massachusetts Medical School4, University of Texas at Austin5, Chinese Academy of Sciences6, University of North Carolina at Chapel Hill7, University of Bergen8, Harvard University9, Imperial College London10
TL;DR: The first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types is presented, revealing novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns.
Abstract: DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation. An extensive map of human DNase I hypersensitive sites, markers of regulatory DNA, in 125 diverse cell and tissue types is described; integration of this information with other ENCODE-generated data sets identifies new relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. This paper describes the first extensive map of human DNaseI hypersensitive sites — markers of regulatory DNA — in 125 diverse cell and tissue types. Integration of this information with other data sets generated by ENCODE (Encyclopedia of DNA Elements) identified new relationships between chromatin accessibility, transcription, DNA methylation and regulatory-factor occupancy patterns. Evolutionary-conservation analysis revealed signatures of recent functional constraint within DNaseI hypersensitive sites.
2,628 citations
TL;DR: A large number of human diseases have been found to be associated with aberrant DNA methylation and the study of these diseases has provided new and fundamental insights into the roles that DNAmethylation and other epigenetic modifications have in development and normal cellular homeostasis.
Abstract: DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. These include embryonic development, transcription, chromatin structure, X chromosome inactivation, genomic imprinting and chromosome stability. Consistent with these important roles, a growing number of human diseases have been found to be associated with aberrant DNA methylation. The study of these diseases has provided new and fundamental insights into the roles that DNA methylation and other epigenetic modifications have in development and normal cellular homeostasis.
2,589 citations
"Relationship between methylome and ..." refers background in this paper
...Indeed, changes in DNA methylation at specific genes are well documented in cancer, and have a profound influence on cancer initiation and progression.(8) Changes in methylation were recently reported to accompany steatohepatitis and precede emergence of hepatocellular carcinoma after infection with hepatitis C virus....
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TL;DR: Methylation changes in cancer are at sites that vary normally in tissue differentiation, consistent with the epigenetic progenitor model of cancer, which proposes that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.
Abstract: For the past 25 years, it has been known that alterations in DNA methylation (DNAm) occur in cancer, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes. However, most studies of cancer methylation have assumed that functionally important DNAm will occur in promoters, and that most DNAm changes in cancer occur in CpG islands. Here we show that most methylation alterations in colon cancer occur not in promoters, and also not in CpG islands, but in sequences up to 2 kb distant, which we term 'CpG island shores'. CpG island shore methylation was strongly related to gene expression, and it was highly conserved in mouse, discriminating tissue types regardless of species of origin. There was a notable overlap (45-65%) of the locations of colon cancer-related methylation changes with those that distinguished normal tissues, with hypermethylation enriched closer to the associated CpG islands, and hypomethylation enriched further from the associated CpG island and resembling that of noncolon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, consistent with the epigenetic progenitor model of cancer, which proposes that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.
2,099 citations
"Relationship between methylome and ..." refers background in this paper
...Differential methylation in cancer is reported as most evident at CGI “shores,”(14,15) defined as regions located up to 2 kb upstream or downstream from a CGI.(15) When we compared methylation profiles in mild to advanced NAFLD, we also found differential methylation was more pronounced at regions flanking TSSs or CGIs (Figure 1B)....
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...Differential methylation in cancer is reported as most evident at CGI “shores,”14,15 defined as regions located up to 2 kb upstream or downstream from a CGI.15 When we compared methylation profiles in mild to advanced NAFLD, we also found differential methylation was more pronounced at regions flanking TSSs or CGIs (Figure 1B)....
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