scholarly journals DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line

2018 ◽  
Vol 60 (2) ◽  
pp. R39-R56 ◽  
Author(s):  
Louise Ruby Høj Illum ◽  
Stine Thorhauge Bak ◽  
Sten Lund ◽  
Anders Lade Nielsen
Keyword(s):  
Dna Methylation ◽  
Metabolic Diseases ◽  
Germ Line ◽  
Epigenetic Inheritance ◽  
Dna Demethylation ◽  
Male Germ Line ◽  
Basic Principles ◽  
Disease Phenotypes ◽  
Non Coding Rna ◽  
Genomic Regions

The global rise in metabolic diseases can be attributed to a complex interplay between biology, behavior and environmental factors. This article reviews the current literature concerning DNA methylation-based epigenetic inheritance (intergenerational and transgenerational) of metabolic diseases through the male germ line. Included are a presentation of the basic principles for DNA methylation in developmental programming, and a description of windows of susceptibility for the inheritance of environmentally induced aberrations in DNA methylation and their associated metabolic disease phenotypes. To this end, escapees, genomic regions with the intrinsic potential to transmit acquired paternal epigenetic information across generations by escaping the extensive programmed DNA demethylation that occurs during gametogenesis and in the zygote, are described. The ongoing descriptive and functional examinations of DNA methylation in the relevant biological samples, in conjugation with analyses of non-coding RNA and histone modifications, hold promise for improved delineation of the effect size and mechanistic background for epigenetic inheritance of metabolic diseases.

scholarly journals De Novo DNA Methylation in the Male Germ Line Occurs by Default but Is Excluded at Sites of H3K4 Methylation

Cell Reports ◽  
2013 ◽  
Vol 4 (1) ◽  
pp. 205-219 ◽  
Author(s):  
Purnima Singh ◽  
Arthur X. Li ◽  
Diana A. Tran ◽  
Nathan Oates ◽  
Eun-Rim Kang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
De Novo ◽  
Germ Line ◽  
H3k4 Methylation ◽  
Male Germ Line

scholarly journals Histone acetylation recruits the SWR1 complex to regulate active DNA demethylation in Arabidopsis

2019 ◽  
Vol 116 (33) ◽  
pp. 16641-16650 ◽  
Author(s):  
Wen-Feng Nie ◽  
Mingguang Lei ◽  
Mingxuan Zhang ◽  
Kai Tang ◽  
Huan Huang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Conceptual Framework ◽  
Histone Acetylation ◽  
Chromatin Remodeling ◽  
Nuclear Protein ◽  
Dna Demethylation ◽  
Specific Target ◽  
Active Dna Demethylation ◽  
Chromatin Remodeling Complex ◽  
Genomic Regions

Active DNA demethylation is critical for controlling the DNA methylomes in plants and mammals. However, little is known about how DNA demethylases are recruited to target loci, and the involvement of chromatin marks in this process. Here, we identify 2 components of the SWR1 chromatin-remodeling complex, PIE1 and ARP6, as required for ROS1-mediated DNA demethylation, and discover 2 SWR1-associated bromodomain-containing proteins, AtMBD9 and nuclear protein X1 (NPX1). AtMBD9 and NPX1 recognize histone acetylation marks established by increased DNA methylation 1 (IDM1), a known regulator of DNA demethylation, redundantly facilitating H2A.Z deposition at IDM1 target loci. We show that at some genomic regions, H2A.Z and DNA methylation marks coexist, and H2A.Z physically interacts with ROS1 to regulate DNA demethylation and antisilencing. Our results unveil a mechanism through which DNA demethylases can be recruited to specific target loci exhibiting particular histone marks, providing a conceptual framework to understand how chromatin marks regulate DNA demethylation.

scholarly journals DNA Methylation in Huntington’s Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 12736
Author(s):  
Nóra Zsindely ◽  
Fruzsina Siági ◽  
László Bodai
Keyword(s):  
Dna Methylation ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mammalian Cells ◽  
Metabolic Diseases ◽  
Single Gene ◽  
Epigenetic Inheritance ◽  
Current Evidence ◽  
Inherited Disease ◽  
Cpg Dinucleotides

Methylation of cytosine in CpG dinucleotides is the major DNA modification in mammalian cells that is a key component of stable epigenetic marks. This modification, which on the one hand is reversible, while on the other hand, can be maintained through successive rounds of replication plays roles in gene regulation, genome maintenance, transgenerational epigenetic inheritance, and imprinting. Disturbed DNA methylation contributes to a wide array of human diseases from single-gene disorders to sporadic metabolic diseases or cancer. DNA methylation was also shown to affect several neurodegenerative disorders, including Huntington’s disease (HD), a fatal, monogenic inherited disease. HD is caused by a polyglutamine repeat expansion in the Huntingtin protein that brings about a multifaceted pathogenesis affecting several cellular processes. Research of the last decade found complex, genome-wide DNA methylation changes in HD pathogenesis that modulate transcriptional activity and genome stability. This article reviews current evidence that sheds light on the role of DNA methylation in HD.

scholarly journals SIZ1-mediated SUMOylation of ROS1 Enhances Its Stability and Positively Regulates Active DNA Demethylation in Arabidopsis

2020 ◽  
Author(s):  
Xiangfeng Kong ◽  
Yechun Hong ◽  
Yi-Feng Hsu ◽  
Huan Huang ◽  
Xue Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Demethylation ◽  
Dna Glycosylase ◽  
Wild Type ◽  
Dna Hypermethylation ◽  
Post Translational Modifications ◽  
Active Dna Demethylation ◽  
Short Summary ◽  
The Stability ◽  
Genomic Regions

AbstractThe 5-methylcytosine DNA glycosylase/lyase REPRESSOR OF SILENCING 1 (ROS1)-mediated active DNA demethylation is critical for shaping the genomic DNA methylation landscape in Arabidopsis. Whether and how the stability of ROS1 may be regulated by post-translational modifications is unknown. Using a methylation-sensitive PCR (CHOP-PCR)-based forward genetic screen for Arabidopsis DNA hypermethylation mutants, we identified the SUMO E3 ligase SIZ1 as a critical regulator of active DNA demethylation. Dysfunction of SIZ1 leads to hyper-methylation at approximately one thousand genomic regions. SIZ1 physically interacts with ROS1 and mediates the SUMOylation of ROS1. The SUMOylation of ROS1 is reduced in siz1 mutant plants. Compared to that in wild type plants, the protein level of ROS1 is significantly decreased, even though there is an increased level of ROS1 transcripts in siz1 mutant plants. Our results suggest that SIZ1 positively regulates active DNA demethylation by promoting the stability of ROS1 protein through SUMOylation.Short SummaryThe 5-methylcytosine DNA glycosylase/lyase REPRESSOR OF SILENCING 1 (ROS1) is indispensable for proper DNA methylation landscape in Arabidopsis. Whether and how the stability of ROS1 may be regulated by post-translational modifications is unknown. Here, we show that SIZ1-mediated SUMOylation of ROS1 enhances its stability and positively regulates active DNA demethylation.

scholarly journals A novel protein complex that regulates active DNA demethylation in Arabidopsis

2020 ◽  
Author(s):  
Pan Liu ◽  
Wen-Feng Nie ◽  
Xiansong Xiong ◽  
Yuhua Wang ◽  
Yuwei Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Protein Complex ◽  
Excision Repair ◽  
Dna Demethylation ◽  
Loss Of Function ◽  
Dna Hypermethylation ◽  
Active Dna Demethylation ◽  
Domain Protein ◽  
Genomic Regions

SUMMARYActive DNA demethylation is critical for altering DNA methylation patterns and regulating gene expression. The 5-methylcytosine DNA glycosylase/lyase ROS1 initiates a base excision repair pathway for active DNA demethylation and is required for the prevention of DNA hypermethylation at thousands of genomic regions in Arabidopsis. How ROS1 is regulated and targeted to specific genomic regions is not well understood. Here, we report the discovery of an Arabidopsis protein complex that contains ROS1, regulates ROS1 gene expression, and likely targets the ROS1 protein to specific genomic regions. ROS1 physically interacts with a WD40 domain protein (RWD40), which in turn interacts with a methyl-DNA binding protein (RMB1) as well as with a zinc finger and homeobox domain protein (RHD1). RMB1 binds to DNA that is methylated in any sequence context, and this binding is necessary for its function in vivo.Loss-of-function mutations in RWD40, RMB1, or RHD1 cause DNA hypermethylation at several tested genomic regions independently of the known ROS1 regulator IDM1. Because the hypermethylated genomic regions include the DNA methylation monitoring sequence in the ROS1 promoter, plants mutated in RWD40, RMB1, or RHD1 show increased ROS1 expression. Importantly, ROS1 binding to the ROS1 promoter requires RWD40, RMB1, and RHD1, suggesting that this complex dictates ROS1 targeting to this locus. Our results demonstrate that ROS1 forms a protein complex with RWD40, RMB1, and RHD1, and that this novel complex regulates active DNA demethylation at several endogenous loci in Arabidopsis.

DNA methylation and epigenetic inheritance

1990 ◽  
Vol 326 (1235) ◽  
pp. 329-338 ◽  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dna Sequences ◽  
Mammalian Cells ◽  
Germ Line ◽  
Experimental System ◽  
Epigenetic Inheritance ◽  
Epigenetic Mechanisms ◽  
Control Of Gene Expression ◽  
Developmental Programme

Classical genetics has revealed the mechanisms for the transmission of genes from generation to generation, but the strategy of the genes in unfolding the developmental programme remains obscure. Epigenetics comprises the study of the mechanisms that impart temporal and spatial control on the activities of all those genes required for the development of a complex organism from the zygote to the adult. Epigenetic changes in gene activity can be studied in relation to DNA methylation in cultured mammalian cells and it is also possible to isolate and characterize mutants with altered DNA methylase activity. Although this experimental system is quite far removed from the epigenetic controls acting during development it does provide the means to clarify the rules governing the silencing of genes by specific DNA methylation and their reactivation by demethylation. This in turn will facilitate studies on the control of gene expression in somatic cells of the developing organism or the adult. The general principles of epigenetic mechanisms can be defined. There are extreme contrasts between instability or switches in gene expression, such as those in stem-line cells, and the stable heritability of a specialized pattern of gene activities. In some situations cell lineages are known to be important, whereas in others coordinated changes in groups of cells have been demonstrated. Control of numbers of cell divisions and the size of organisms, or parts of organisms, is also essential. The epigenetic determination of gene expression can be reversed or reprogrammed in the germ line. The extent to which methylation or demethylation of specific DNA sequences can help explain these basic epigenetic mechanisms is briefly reviewed.

scholarly journals Timing and Sequence Requirements Defined for Embryonic Maintenance of Imprinted DNA Methylation at Rasgrf1

2006 ◽  
Vol 26 (24) ◽  
pp. 9564-9570 ◽  
Author(s):  
Rebecca Holmes ◽  
Yanjie Chang ◽  
Paul D. Soloway
Keyword(s):  
Dna Methylation ◽  
Germ Line ◽  
Direct Repeat ◽  
Repeat Sequence ◽  
Paternal Allele ◽  
Imprinted Genes ◽  
Male Germ Line ◽  
Specific Expression ◽  
Morula Stage ◽  
Allele Specific

ABSTRACT Epigenetic programming is critical for normal development of mammalian embryos. Errors cause misexpression of genes and aberrant development (E. Li, C. Beard, and R. Jaenisch, Nature 366:362-365, 1993). Imprinted genes are important targets of epigenetic regulation, but little is known about how the epigenetic patterns are established in the parental germ lines and maintained in the embryo. Paternal allele-specific expression at the imprinted Rasgrf1 locus in mice is controlled by paternal allele-specific methylation at a differentially methylated domain (DMD). DMD methylation is in turn controlled by a direct repeat sequence immediately downstream of the DMD which is required for establishing Rasgrf1 methylation in the male germ line (B. J. Yoon et al., Nat. Genet. 30:92-96, 2002). To determine if these repeats have a role in methylation maintenance, we developed a conditional deletion of the repeat sequence in mice and showed that the repeats are also required during a narrow interval to maintain paternal methylation of Rasgrf1 in developing embryos. Removing the repeats upon fertilization caused a total loss of methylation by the morula stage, but by the epiblast stage, the repeats were completely dispensable for methylation maintenance. This developmental interval coincides with genome-wide demethylation and remethylation in mice which most imprinted genes resist. Our data show that the Rasgrf1 repeats serve at least two functions: first, to establish Rasgrf1 DNA methylation in the male germ line, and second, to resist global demethylation in the preimplantation embryo.

scholarly journals Active DNA demethylation regulates tracheary element differentiation in Arabidopsis

2020 ◽  
Vol 6 (26) ◽  
pp. eaaz2963
Author(s):  
Wei Lin ◽  
Linhua Sun ◽  
Run-Zhou Huang ◽  
Wenjie Liang ◽  
Xinyu Liu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Tracheary Element ◽  
Dna Demethylation ◽  
Epigenetic Mechanism ◽  
Dna Glycosylases ◽  
Tracheary Element Differentiation ◽  
Xylem Development ◽  
Active Dna Demethylation ◽  
Genomic Regions

DNA demethylation is important for the erasure of DNA methylation. The role of DNA demethylation in plant development remains poorly understood. Here, we found extensive DNA demethylation in the CHH context around pericentromeric regions and DNA demethylation in the CG, CHG, and CHH contexts at discrete genomic regions during ectopic xylem tracheary element (TE) differentiation. While loss of pericentromeric methylation occurs passively, DNA demethylation at a subset of regions relies on active DNA demethylation initiated by DNA glycosylases ROS1, DML2, and DML3. The ros1 and rdd mutations impair ectopic TE differentiation and xylem development in the young roots of Arabidopsis seedlings. Active DNA demethylation targets and regulates many genes for TE differentiation. The defect of xylem development in rdd is proposed to be caused by dysregulation of multiple genes. Our study identifies a role of active DNA demethylation in vascular development and reveals an epigenetic mechanism for TE differentiation.

scholarly journals Estrogen signaling, through estrogen receptor β, regulates DNA methylation and its machinery in male germ line in adult rats

Epigenetics ◽  
2017 ◽  
Vol 12 (6) ◽  
pp. 476-483 ◽  
Author(s):  
Kushaan Dumasia ◽  
Anita Kumar ◽  
Sharvari Deshpande ◽  
Nafisa H. Balasinor
Keyword(s):  
Dna Methylation ◽  
Estrogen Receptor ◽  
Germ Line ◽  
Estrogen Receptor Β ◽  
Estrogen Signaling ◽  
Male Germ Line ◽  
Adult Rats

96 AN IMMUNOHISTOCHEMICAL STUDY ON MARKERS OF PLURIPOTENCY AND DNA METHYLATION IN THE DEVELOPING PORCINE GERM LINE

2009 ◽  
Vol 21 (1) ◽  
pp. 148
Author(s):  
M. Vejlsted ◽  
S. M. W. Hyldig ◽  
P. Maddox-Hyttel
Keyword(s):  
Dna Methylation ◽  
Germ Cells ◽  
Germ Line ◽  
Immunohistochemical Study ◽  
Methylation Status ◽  
Dna Demethylation ◽  
Santa Cruz ◽  
The Third ◽  
Pluripotency Markers ◽  
Gestational Week

Reprogramming of the germ line genome is a fundamental molecular process involving DNA demethylation. This has been demonstrated in the mouse (Seki Y et al. 2005 Dev. Biol. 278, 440–458), but has not yet been studied in the pig. From a large collection of porcine embryos/fetuses 2 to 7 weeks post-insemination (p.i.), a total of 35 randomly selected specimens from the end of the second (n = 10), third (n = 10), fourth (n = 5), and seventh (n = 10) gestational week were selected for an immunohistochemical study on pluripotency markers and DNA methylation in the developing germ line. Intact embryos and isolated developing gonads were paraffin embedded, sectioned (5 to 15 μm) and evaluated for the expression of markers of pluripotency [OCT4 (sc-8628, Santa Cruz Biotech., Santa Cruz, CA), Nanog (500-P236, PeproTech EC, Rocky Hill, NJ), and SOX2 (MAB2018, R&D Systems, Wiesbaden, Germany)], DNA methylation [5-methyl cytidine (ab10805, Abcam, Cambridge, MA)], and meiosis [SCP-3 (generous gift from C. Heyting)]. Heat-induced epitope retrieval (HIER) in an alkaline (pH 8.2) EDTA buffer (Shi SR et al. 2001 J. Histochem. Cytochem. 49, 931–937) and confocal laser scanning microscopy allowed for the evaluation of germ cells co-expressing OCT4 and 5-methyl cytidine. The expression of Nanog and SOX2 was found to be better visualized using HIER in an acidic (pH 6.0) citrate buffer. Isolated and clustered primordial germ cells (PGC) were identified by OCT4 labeling early during gastrulation in embryos around 2 weeks of age p.i. The amount of methylated DNA in PGC appeared similar to that in the nuclei of neighboring somatic cells at this stage. During colonization of the genital ridges, in embryos at the end of the third gestational week, this global DNA methylation status seemed to markedly decrease in PGC, remaining low in the gonadal maturing germ cells. Around onset of meiosis, in fetuses at the seventh gestational week, germ cells in 3 out of 5 female specimens studied had ceased to express markers of pluripotency. In contrast, such markers appeared to be retained in germ cells of male siblings. In conclusion, expression of pluripotency markers during porcine germ line development appears similar to what has been described in the mouse with expression ceasing at the beginning of meiosis in the female but not in the male fetus. Further, the timing of germ line DNA demethylation appears similar between the 2 species. In the mouse, PGC entering the genital ridges soon initiate meiosis, whereas in the pig, these events are separated by a 3-week period. The connection between porcine germ line pluripotency and DNA methylation status during the third to fourth week of development p.i. is presently being thoroughly investigated.

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