scholarly journals Heterozygous loss of ZBTB38 leads to early embryonic lethality in mice via suppressing Nanog and Sox2

2021 ◽  
Author(s):  
Eishou Matsuda ◽  
Miki Nishio ◽  
Takuya Matsuura ◽  
Shunya Hibi ◽  
Shiomi Ohta ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Proliferation ◽  
Gene Expression Regulation ◽  
Epigenetic Modification ◽  
Embryonic Lethality ◽  
Biological Processes ◽  
Es Cell ◽  
Nanog Expression ◽  
Early Embryonic Lethality ◽  
Single Allele

Mammalian DNA methylation is an epigenetic modification which is involved in various biological processes, including gene expression regulation. In mice, methyltransferases are responsible for DNA methylation, which are critical for early embryogenesis. However, the significance of methyl-CpG binding proteins (MBPs) that bind methylated CpG remains largely unknown. We previously demonstrated that ZBTB38/CIBZ-a zinc finger type of MBP-is required for ES cell proliferation by positively regulating Nanog expression. However, the physiological function of ZBTB38 remains unclear. In this study, we generated conditional ZBTB38 knockout mice using Cre-loxP technology. Unexpectedly, our results showed that germline loss of the ZBTB38 single allele resulted in decreased epiblast cell proliferation and increased apoptosis shortly after implantation, leading to early embryonic lethality. We found that heterozygous loss of ZBTB38 reduced the expression of Nanog, Sox2, and the genes responsible for epiblast proliferation, differentiation, and cell viability. Despite this lethal phenotype, ZBTB38 is dispensable for ES cell establishment and identity. Together, these findings indicate that ZBTB38 is essential for early embryonic development, providing new insights into the roles of MBP in implantation.

scholarly journals Genome-wide DNA methylation profiles of porcine ovaries in estrus and proestrus

2018 ◽  
Vol 50 (9) ◽  
pp. 714-723 ◽  
Author(s):  
Xiaolong Zhou ◽  
Songbai Yang ◽  
Feifei Yan ◽  
Ke He ◽  
Ayong Zhao
Keyword(s):  
Dna Methylation ◽  
Epigenetic Modification ◽  
Cpg Islands ◽  
Biological Processes ◽  
Hormone Regulation ◽  
Methylated Dna ◽  
Coding Regions ◽  
Genome Wide ◽  
Differentially Methylated Genes ◽  
Flanking Regions

DNA methylation is an important epigenetic modification involved in the estrous cycle and the regulation of reproduction. Here, we investigated the genome-wide profiles of DNA methylation in porcine ovaries in proestrus and estrus using methylated DNA immunoprecipitation sequencing. The results showed that DNA methylation was enriched in intergenic and intron regions. The methylation levels of coding regions were higher than those of the 5′- and 3′-flanking regions of genes. There were 4,813 differentially methylated regions (DMRs) of CpG islands in the estrus vs. proestrus ovarian genomes. Additionally, 3,651 differentially methylated genes (DMGs) were identified in pigs in estrus and proestrus. The DMGs were significantly enriched in biological processes and pathways related to reproduction and hormone regulation. We identified 90 DMGs associated with regulating reproduction in pigs. Our findings can serve as resources for DNA methylome research focused on porcine ovaries and further our understanding of epigenetically regulated reproduction in mammals.

scholarly journals Loss of Borealin/DasraB leads to defective cell proliferation, p53 accumulation and early embryonic lethality

2008 ◽  
Vol 125 (5-6) ◽  
pp. 441-450 ◽  
Author(s):  
Yasunari Yamanaka ◽  
Toshio Heike ◽  
Tomohiro Kumada ◽  
Minoru Shibata ◽  
Yuki Takaoka ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Embryonic Lethality ◽  
Early Embryonic Lethality

scholarly journals Sex-specific DNA methylation changes in Alzheimer’s disease pathology

2021 ◽  
Author(s):  
Lanyu Zhang ◽  
Juan Young ◽  
Lissette Gomez ◽  
Tiago Silva ◽  
Michael Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Epigenetic Modification ◽  
Association Studies ◽  
Specific Treatment ◽  
Type I ◽  
Braak Stage ◽  
Biological Processes ◽  
Specific Manner

Abstract Sex is an important factor that contributes to the clinical and biological heterogeneities in Alzheimer’s disease (AD), but the regulatory mechanisms underlying sex disparity in AD are still not well understood. DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD. We performed the first large-scale sex-specific meta-analysis of DNA methylation changes in AD, by re-analyzing four recent epigenome-wide association studies totaling more than 1000 postmortem prefrontal cortex brain samples using a uniform analytical pipeline. For each cohort we employed two complementary analytical strategies, a sex-stratified analysis that examined methylation-Braak stage associations in male and female samples separately, and a sex-by-Braak stage interaction analysis that compared the magnitude of these associations between different sexes. Our analysis uncovered 14 novel CpGs, mapped to genes such as TMEM39A and TNXB that are associated with AD in a sex-specific manner. TMEM39A is known to be involved in inflammation, dysregulated type I interferon responses, and other immune processes. TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain. Moreover, for many previously implicated AD genes, such as MBP and AZU1, our analysis provided the new insights that they were predominately driven by effects in only one sex. These sex-specific DNA methylation changes were enriched in divergent biological processes such as integrin activation in females and complement activation in males. Importantly, a number of drugs commonly prescribed for AD patients also targeted these genes with sex-specific DNA methylation changes. Our study implicated multiple new loci and biological processes that affected AD in a sex-specific manner and highlighted the importance of sex-specific treatment regimens for AD patients.

scholarly journals Epigenetic regulations through DNA methylation and hydroxymethylation: clues for early pregnancy in decidualization

2014 ◽  
Vol 5 (2) ◽  
pp. 95-107 ◽  
Author(s):  
Fei Gao ◽  
Sanjoy K. Das
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cell Fate ◽  
High Throughput Sequencing ◽  
Gene Expression Regulation ◽  
Epigenetic Modification ◽  
Regulation Of Gene Expression ◽  
Reproductive Organ ◽  
Epigenetic Changes ◽  
Dynamic Regulation

AbstractDNA methylation at cytosines is an important epigenetic modification that participates in gene expression regulation without changing the original DNA sequence. With the rapid progress of high-throughput sequencing techniques, whole-genome distribution of methylated cytosines and their regulatory mechanism have been revealed gradually. This has allowed the uncovering of the critical roles played by DNA methylation in the maintenance of cell pluripotency, determination of cell fate during development, and in diverse diseases. Recently, rediscovery of 5-hydroxymethylcytosine, and other types of modification on DNA, have uncovered more dynamic aspects of cell methylome regulation. The interaction of DNA methylation and other epigenetic changes remodel the chromatin structure and determine the state of gene transcription, not only permanently, but also transiently under certain stimuli. The uterus is a reproductive organ that experiences dramatic hormone stimulated changes during the estrous cycle and pregnancy, and thus provides us with a unique model for studying the dynamic regulation of epigenetic modifications. In this article, we review the current findings on the roles of genomic DNA methylation and hydroxymethylation in the regulation of gene expression, and discuss the progress of studies for these epigenetic changes in the uterus during implantation and decidualization.

Low Oxygen Consumption is Related to a Hypomethylation and an Increased Secretion of IL-6 in Obese Subjects with Sleep Apnea-Hypopnea Syndrome

2017 ◽  
Vol 71 (1-2) ◽  
pp. 16-25 ◽  
Author(s):  
Amaya Lopez-Pascual ◽  
Arrate Lasa ◽  
María P. Portillo ◽  
Fernando Arós ◽  
María L. Mansego ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Oxygen Consumption ◽  
Sleep Apnea ◽  
Gene Expression Regulation ◽  
Epigenetic Modification ◽  
Fat Free Mass ◽  
Low Oxygen ◽  
Age Related ◽  
Obese Subjects ◽  
Hypopnea Syndrome

Background: Deoxyribonucleic acid (DNA) methylation is an epigenetic modification involved in gene expression regulation, usually via gene silencing, which contributes to the risks of many multifactorial diseases. The aim of the present study was to analyze the influence of resting oxygen consumption on global and gene DNA methylation as well as protein secretion of inflammatory markers in blood cells from obese subjects with sleep apnea-hypopnea syndrome (SAHS). Methods: A total of 44 obese participants with SAHS were categorized in 2 groups according to their resting oxygen consumption. DNA methylation levels were evaluated using a methylation-sensitive high resolution melting approach. Results: The analyzed interleukin 6 (IL6) gene cytosine phosphate guanine (CpG) islands showed a hypomethylation, while serum IL-6 was higher in the low compared to the high oxygen consumption group (p < 0.05). Moreover, an age-related loss of DNA methylation of tumor necrosis factor (B = -0.82, 95% CI -1.33 to -0.30) and long interspersed nucleotide element 1 (B = -0.46; 95% CI -0.87 to -0.04) gene CpGs were found. Finally, studied CpG methylation levels of serpin peptidase inhibitor, clade E member 1 (r = 0.43; p = 0.01), and IL6 (r = 0.41; p = 0.02) were positively associated with fat-free mass. Conclusions: These findings suggest a potential role of oxygen in the regulation of inflammatory genes. Oxygen consumption measurement at rest could be proposed as a clinical biomarker of metabolic health.

scholarly journals Sex-specific DNA methylation changes in Alzheimer’s disease pathology

2021 ◽  
Author(s):  
Lanyu Zhang ◽  
Juan I. Young ◽  
Lissette Gomez ◽  
Tiago C. Silva ◽  
Michael A. Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Dna Methylation ◽  
Epigenetic Modification ◽  
Association Studies ◽  
Specific Treatment ◽  
Type I ◽  
Braak Stage ◽  
Biological Processes ◽  
Specific Manner

AbstractSex is an important factor that contributes to the clinical and biological heterogeneities in Alzheimer’s disease (AD), but the regulatory mechanisms underlying sex disparity in AD are still not well understood. DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD. We performed the first large-scale sex-specific meta-analysis of DNA methylation changes in AD, by re-analyzing four recent epigenome-wide association studies totaling more than 1000 postmortem prefrontal cortex brain samples using a uniform analytical pipeline. For each cohort we employed two complementary analytical strategies, a sex-stratified analysis that examined methylation-Braak stage associations in male and female samples separately, and a sex-by-Braak stage interaction analysis that compared the magnitude of these associations between different sexes. Our analysis uncovered 14 novel CpGs, mapped to genes such as TMEM39A and TNXB that are associated with AD in a sex-specific manner. TMEM39A is known to be involved in inflammation, dysregulated type I interferon responses, and other immune processes. TNXB encodes tenascin proteins, which are extracellular matrix glycoproteins demonstrated to modulate synaptic plasticity in the brain. Moreover, for many previously implicated AD genes, such as MBP and AZU1, our analysis provided the new insights that they were predominately driven by effects in only one sex. These sex-specific DNA methylation changes were enriched in divergent biological processes such as integrin activation in females and complement activation in males. Importantly, a number of drugs commonly prescribed for AD patients also targeted these genes with sex-specific DNA methylation changes. Our study implicated multiple new loci and biological processes that affected AD in a sex-specific manner and highlighted the importance of sex-specific treatment regimens for AD patients.

scholarly journals p53 Accumulation, defective cell proliferation, and early embryonic lethality in mice lacking tsg101

2001 ◽  
Vol 98 (4) ◽  
pp. 1859-1864 ◽  
Author(s):  
J. Ruland ◽  
C. Sirard ◽  
A. Elia ◽  
D. MacPherson ◽  
A. Wakeham ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Embryonic Lethality ◽  
Early Embryonic Lethality

scholarly journals Differential Recruitment of Methylated CpG Binding Domains by the Orphan Receptor GCNF Initiates the Repression and Silencing of Oct4 Expression

2006 ◽  
Vol 26 (24) ◽  
pp. 9471-9483 ◽  
Author(s):  
Peili Gu ◽  
Damien Le Menuet ◽  
Arthur C.-K. Chung ◽  
Austin J. Cooney
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Epigenetic Modification ◽  
Es Cells ◽  
Somatic Cells ◽  
Embryonic Stem ◽  
Orphan Receptor ◽  
Proximal Promoter ◽  
Es Cell ◽  
Oct4 Expression

ABSTRACT The pluripotent factor Oct4 is a key transcription factor that maintains embryonic stem (ES) cell self-renewal and is down-regulated upon the differentiation of ES cells and silenced in somatic cells. A combination of cis elements, transcription factors, and epigenetic modifications, such as DNA methylation, are involved in the regulation of Oct4 gene expression. Here we show that the orphan nuclear receptor GCNF initiates Oct4 repression and DNA methylation by the differential recruitment of MBD (methylated CpG binding domain) factors to the promoter. Compared with wild-type ES cells and gastrulating embryos, Oct4 repression is lost and its proximal promoter is significantly hypomethylated in RA-differentiated GCNF−/− ES cells. The Oct4 gene is reexpressed in some somatic cells of GCNF−/− embryos, showing that it has not been properly silenced coincident with reduced DNA methylation of its promoter. Efforts to characterize mediators of GCNF's repressive function and DNA methylation of the Oct4 promoter identified methyl-DNA binding proteins, MBD3 and MBD2, as GCNF-interacting factors. In P19 and ES cells, upon differentiation, endogenous GCNF binds to the Oct4 proximal promoter and differentially recruits MBD3 and MBD2. In differentiated GCNF−/− ES cells, recruitment of MBD3 and MBD2 to the Oct4 promoter is lost, and repression of Oct4 expression and DNA methylation fails to occur. RNA interference-mediated knockdown of MBD3 and/or MBD2 expression results in reduced Oct4 repression in differentiated P19 and ES cells. Repression of Oct4 expression and recruitment of MBD3 are maintained in de novo DNA methylation-deficient ES cells (Dnmt3A/3B-null cells), while MBD2 recruitment is lost. Thus, recruitment of MBD3 and MBD2 by GCNF links two events, gene-specific repression and DNA methylation, which occur differentially at the Oct4 promoter. GCNF initiates the repression and epigenetic modification of Oct4 gene during ES cell differentiation.

scholarly journals DNA methylation-linked chromatin accessibility affects genomic architecture in Arabidopsis

2021 ◽  
Vol 118 (5) ◽  
pp. e2023347118
Author(s):  
Zhenhui Zhong ◽  
Suhua Feng ◽  
Sascha H. Duttke ◽  
Magdalena E. Potok ◽  
Yiwei Zhang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Organization ◽  
Epigenetic Modification ◽  
Chromatin Accessibility ◽  
Biological Processes ◽  
Profound Impact ◽  
Chromatin Interactions ◽  
Genomic Architecture ◽  
Genome Wide ◽  
Different Types

DNA methylation is a major epigenetic modification found across species and has a profound impact on many biological processes. However, its influence on chromatin accessibility and higher-order genome organization remains unclear, particularly in plants. Here, we present genome-wide chromatin accessibility profiles of 18 Arabidopsis mutants that are deficient in CG, CHG, or CHH DNA methylation. We find that DNA methylation in all three sequence contexts impacts chromatin accessibility in heterochromatin. Many chromatin regions maintain inaccessibility when DNA methylation is lost in only one or two sequence contexts, and signatures of accessibility are particularly affected when DNA methylation is reduced in all contexts, suggesting an interplay between different types of DNA methylation. In addition, we found that increased chromatin accessibility was not always accompanied by increased transcription, suggesting that DNA methylation can directly impact chromatin structure by other mechanisms. We also observed that an increase in chromatin accessibility was accompanied by enhanced long-range chromatin interactions. Together, these results provide a valuable resource for chromatin architecture and DNA methylation analyses and uncover a pivotal role for methylation in the maintenance of heterochromatin inaccessibility.

scholarly journals Whole genome analysis of the methylome and hydroxymethylome in normal and malignant lung and liver

2016 ◽  
Author(s):  
Xin Li ◽  
Yun Liu ◽  
Tal Salz ◽  
Kasper D. Hansen ◽  
Andrew Feinberg
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Gene Expression Regulation ◽  
Cpg Island ◽  
Epigenetic Modification ◽  
Dna Demethylation ◽  
Regulatory Function ◽  
Whole Genome ◽  
Strong Positive Correlation ◽  
Active Genes

AbstractDNA methylation at the 5-postion of cytosine (5mC) is a well-established epigenetic modification which regulates gene expression and cellular plasticity in development and disease. The ten-eleven translocation (TET) gene family is able to oxidize 5mC to 5-hydroxymethyl-cytosine (5hmC), providing an active mechanism for DNA demethylation, and may also provide its own regulatory function. Here we applied oxidative bisulfite sequencing to generate whole-genome DNA methylation and hydroxymethylation maps at single-base resolution in paired human liver and lung normal and cancer. We found that 5hmC is significantly enriched in CpG island (CGI) shores while depleted in CGIs themselves, in particular at active genes, resulting in a 5hmC but not 5mC bimodal distribution around CGI corresponding to H3K4me1 marks. Hydroxymethylation on promoters, gene bodies, and transcription termination regions showed strong positive correlation with gene expression within and across tissues, suggesting that 5hmC is a mark of active genes and could play a role gene expression mediated by DNA demethylation. Comparative analysis of methylomes and hydroxymethylomes revealed that 5hmC is significantly enriched in both tissue specific DMRs (t-DMRs) and cancer specific DMRs (c-DMRs), and 5hmC is negatively correlated with methylation changes, particularly in non-CGI associated DMRs. Together these findings indicate that changes in 5mC as well as in 5hmC and coupled to H3K4me1 correspond to differential gene expression in tissues and matching tumors, revealing an intricate gene expression regulation through interplay of methylome, hydroxyl-methylome, and histone modifications.

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