scholarly journals Characterization of Timed Changes in Hepatic Copper Concentrations, Methionine Metabolism, Gene Expression, and Global DNA Methylation in the Jackson Toxic Milk Mouse Model of Wilson Disease

2014 ◽  
Vol 15 (5) ◽  
pp. 8004-8023 ◽  
Author(s):  
Anh Le ◽  
Noreene Shibata ◽  
Samuel French ◽  
Kyoungmi Kim ◽  
Kusum Kharbanda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Mouse Model ◽  
Wilson Disease ◽  
Global Dna Methylation ◽  
Methionine Metabolism ◽  
Hepatic Copper ◽  
Metabolism Gene

scholarly journals Wilson disease: intersecting DNA methylation and histone acetylation regulation of gene expression in a mouse model of hepatic copper accumulation

2021 ◽  
Author(s):  
Gaurav V. Sarode ◽  
Kari Neier ◽  
Noreene M. Shibata ◽  
Yuanjun Shen ◽  
Dmitry A Goncharov ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Mouse Model ◽  
Histone Acetylation ◽  
Wilson Disease ◽  
Metabolic Pathways ◽  
Histone Deacetylases ◽  
Copper Accumulation ◽  
Copper Transporter ◽  
Pathogenic Variants

AbstractThe pathogenesis of Wilson disease (WD) is multi-factorial, involving hepatic and brain copper accumulation due to pathogenic variants affecting the ATP7B gene and downstream epigenetic and metabolic mechanisms. Prior DNA methylation investigations in human WD liver and blood and in a WD mouse model revealed an epigenetic signature of WD, including alterations in the histone deacetylase HDAC5. To test the hypothesis that histone acetylation is altered with respect to copper overload and aberrant DNA methylation in WD, we investigated class IIa histone deacetylases (HDAC4 and HDAC5) and H3K9/H3K27 histone acetylation in the Jackson Laboratory toxic milk (tx-j) mouse model of WD compared to C3HeB/FeJ (C3H) control in response to 3 treatments: 60% kcal fat diet (HFD), D-penicillamine (PCA, copper chelator), and choline (methyl group donor). HDAC5 levels significantly increased in 9-week tx-j livers after 8 days of HFD compared to chow. In 24-week tx-j livers, HDAC4/5 levels were reduced 5- to 10-fold compared to C3H likely through mechanisms involving HDAC phosphorylation. HDAC4/5 levels were also affected by disease progression and accompanied by increased acetylation. PCA and choline partially restored HDAC4, HDAC5, H3K9ac, and H3K27ac levels to that of CH3 liver. Integrated RNA and chromatin immunoprecipitation sequencing analyses revealed genes regulating energy metabolism and cellular stress/development were, in turn, regulated by histone acetylation in tx-j mice compared to C3H, with Pparα and Pparγ among the most relevant targets. These results suggest dietary modulation of class IIa HDAC4/5, and subsequent H3K9/H3K27 acetylation/deacetylation, can regulate gene expression in key metabolic pathways in the pathogenesis of WD.Significance StatementWilson disease is considered a monogenic disease caused by pathogenic variants in the ATP7B copper transporter, resulting in hepatic and brain copper accumulation. Given the lack of genotype-phenotype correlation, evidence of epigenetic and metabolic mechanisms regulating phenotype in patients and in animal models could explain the high phenotype variability observed in WD. In this study, we identify class IIa histone deacetylases as players involved in the epigenetic regulation of key metabolic pathways that can affect WD severity as well as targets sensitive to dietary modulations, which is an important characteristic for designing effective and feasible therapies. Understanding the epigenetic mechanisms in WD pathogenesis contributes to a better understanding of the phenotypic variability in WD and other common liver conditions.

scholarly journals Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease

Epigenetics ◽  
2013 ◽  
Vol 9 (2) ◽  
pp. 286-296 ◽  
Author(s):  
Valentina Medici ◽  
Noreene M Shibata ◽  
Kusum K Kharbanda ◽  
Mohammad S Islam ◽  
Carl L Keen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Mouse Model ◽  
Wilson Disease ◽  
Fetal Liver ◽  
Liver Copper ◽  
Neonatal Growth

scholarly journals Integrated Analysis of Global DNA Methylation and Transcription Reveals a Leukemia Subtype with Extreme Hypermethylation Associated with Silencing of Regulators of Differentiation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2608-2608
Author(s):  
Claudia Gebhard ◽  
Roger Mulet-Lazaro ◽  
Lucia Schwarzfischer ◽  
Dagmar Glatz ◽  
Margit Nuetzel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Promoter Methylation ◽  
Research Funding ◽  
Promoter Hypermethylation ◽  
Ctcf Binding ◽  
P Value ◽  
Global Dna Methylation ◽  
Employment Equity ◽  
Equity Ownership

Abstract Acute myeloid leukemia (AML) represents a highly heterogeneous myeloid stem cell disorder classified based on various genetic defects. Besides genetic alterations, epigenetic changes are recognized as an additional mechanism contributing to leukemogenesis, but insight into the latter process remains minor. Using a combination of Methyl-CpG-Immunoprecipitation (MCIp-chip) and MALDI-TOF analysis of bisulfite-treated DNA in a cohort of 196 AML patients we previously demonstrated that (cyto)genetically defined AML subtypes, including CBFB-MYH11, AML-ETO, NPM1-mut, CEBPA-mut or IDH1/2-mut subtypes, express specific DNA-methylation profiles (Gebhard et al, Leukemia, 2018). A fraction of AML patients (5/196) displayed a unique abnormal hypermethylation profile that was completely distinct from any other AML subtype. These patients present immature leukemia (FAB M0, M1) with various chromosomal aberrations but very few mutations (e.g. no IDH1/2, KRAS, DNMT3A) that might explain the CpG island methylator phenotype (CIMP) phenotype. The CIMP patients showed high resemblance with a recently reported CEBPA methylated subgroup (Wouters et al, 2007 and Figueroa et al, 2009), which we confirmed by MCIp-chip and MALDI-TOF analysis. To explore the whole range of epigenetic alterations in the CIMP-AML patients we performed in-depth global DNA methylation and gene expression analyses (MCIp-seq and RNA-seq) in 45 AML and 12 CIMP patients from both studies. Principle component analysis and t-distributed stochastic neighbor embedding (t-SNE) revealed that CIMP patients express a unique DNA-methylation and gene-expression signature that separated them from all other AMLs. We could discriminate promoter methylation from non-promoter methylation by selecting MCIp-seq peaks within 3kb around TSS. Promoter hypermethylation was highly associated with repression of genes (PCC = -0.053, p-value = 0.00075). Hypermethylation of non-promoter regions was more strongly associated with upregulation of genes (PCC = 0.046, p-value = 4.613e-06). Interestingly, differentially methylated regions also showed a positive association with myeloid lineage CTCF binding sites (27% vs 18% expected, p-value < 2.2e-16 in a chi-square test of independence). Methylation of CTCF sites causes loss of CTCF binding, which has been reported to disrupt boundaries between so-called topologically associated domains (TADs), allowing enhancers located in a particular TAD to become accessible to genes in adjacent TADs and affect their transcription. Whether this is the case is under investigation. In this study we particularly focused on the role of hypermethylation of promoters in CIMP-AMLs. Promoters of many transcriptional regulators that are involved in the differentiation of myeloid lineages of which several are frequently mutated in AML were hypermethylated and repressed, including CEBPA, CEBPD, IRF8, GATA2, KLF4, MITF or MAFB. Notably, HMGA2, a critical regulator of myeloid progenitor expansion, exhibited the largest degree of CIMP promoter hypermethylation compared to the other AMLs, accompanied by a reduction in gene expression. Moreover, multiple members of the HOXB family and KLF1 (erythroid differentiation) were methylated and repressed as well. In addition, these patients frequently showed hypermethylation of many chromatin factors (e.g. LMNA, CHD7 or TET2). Hypermethylation of the TET2 promoter could result in a loss of maintenance DNA demethylation and therefore successive hypermethylation at CpG islands. We carried out regulome-capture-bisulfite sequencing on CIMP-AMLs compared to other AML samples and normal blood cell controls and confirmed methylation of the same transcription and chromatin factor promoters. We conclude that these leukemias represent very primitive HSCPs which are blocked in differentiation into multiple hematopoietic lineages, due to the absence of regulators of these lineages. Although the underlying cause for the extreme hypermethylation signature is still subject to ongoing studies, the consequence of promoter hypermethylation is silencing of key lineage regulators causing the differentiation arrest in these cells. We argue that these patients may particularly benefit from therapies that revert DNA methylation. Disclosures Ehninger: Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

scholarly journals Early Maternal Alcohol Consumption Alters Hippocampal DNA Methylation, Gene Expression and Volume in a Mouse Model

PLoS ONE ◽  
2015 ◽  
Vol 10 (5) ◽  
pp. e0124931 ◽  
Author(s):  
Heidi Marjonen ◽  
Alejandra Sierra ◽  
Anna Nyman ◽  
Vladimir Rogojin ◽  
Olli Gröhn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Alcohol Consumption ◽  
Mouse Model ◽  
Maternal Alcohol ◽  
Maternal Alcohol Consumption

CHARACTERIZATION OF GLOBAL DNA METHYLATION AT LINE-1 IN A COHORT OF URBAN ASTHMATIC CHILDREN WITH A GRADIENT OF EXPOSURE TO HIGHWAYS

2011 ◽  
Vol 2011 (1) ◽  
Author(s):  
Toby C. Lewis ◽  
Laura Rozek ◽  
Adrienne Van Zomeren-Dohm ◽  
Bhramar Mukherjee ◽  
Xiaodan Ren ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Global Dna Methylation ◽  
Asthmatic Children

scholarly journals * Host iron metabolism gene expression in ins-gas mouse model of helicobacter infection

Gut ◽  
2011 ◽  
Vol 60 (Suppl 1) ◽  
pp. A107-A107
Author(s):  
M. J. Thomson ◽  
D. M. Pritchard ◽  
S. A. Boxall ◽  
A. Varro ◽  
J. E. Crabtree
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Iron Metabolism ◽  
Metabolism Gene

scholarly journals Intergenerational Effect of Early Life Exposure to Permethrin: Changes in Global DNA Methylation and in Nurr1 Gene Expression

Toxics ◽  
2015 ◽  
Vol 3 (4) ◽  
pp. 451-461 ◽  
Author(s):  
Laura Bordoni ◽  
Cinzia Nasuti ◽  
Maria Mirto ◽  
Fabio Caradonna ◽  
Rosita Gabbianelli
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Early Life ◽  
Global Dna Methylation ◽  
Early Life Exposure ◽  
Intergenerational Effect

scholarly journals Genome‑wide analysis of DNA methylation and gene expression changes in an ovalbumin‑induced asthma mouse model

2020 ◽  
Vol 22 (3) ◽  
pp. 1709-1716
Author(s):  
Joong‑Sun Kim ◽  
In‑Sik Shin ◽  
Na‑Rae Shin ◽  
Jae‑Yong Nam ◽  
Chul Kim
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Mouse Model ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Asthma Mouse Model
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