Reprogramming of miR-181a/DNA methylation patterns contribute to the maternal nicotine exposure-induced fetal programming of cardiac ischemia-sensitive phenotype in postnatal life

Abstract It has been well documented that fetal programming, caused by changes to the maternal environment during pregnancy, can impact the overall health and growth of the offspring in livestock and non-livestock species alike. These effects are observed in the F1 offspring as well as across subsequent generations; however, the mechanisms by which this occurs are still poorly understood. Epigenetics is one of the many mechanisms that is hypothesized to have a role in fetal programming and may be mediating the observed effects across multiple generations. It has been demonstrated by others that DNA methylation patterns can be altered by an individuals’ diet and that the pancreas is vulnerable to the effects of fetal programming. Therefore, we evaluated the effects of poor maternal nutrition during gestation on the pancreas tissue of lambs. We have demonstrated that maternal under- or overnutrition during gestation alters the DNA methylation patterns of the offspring pancreas tissue with these effects being diet dependent and sex specific. We have also begun evaluating the effects of maternal diet in murine models using whole-genome bisulfite sequencing to compare species differences and determine if there are any changes conserved across species. This will allow us to focus on a smaller number of critical factors in individuals as they age and across multiple generations in livestock species such as sheep and cattle. From these data we will be able to elucidate the role DNA methylation has in mediating the effects of maternal programming in the pancreas tissue.

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DNA Methylation Patterning and the Regulation of Beta Cell Homeostasis

Frontiers in Endocrinology ◽

10.3389/fendo.2021.651258 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nazia Parveen ◽

Sangeeta Dhawan

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Beta Cell ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Expression Patterns ◽

Cell Phenotype ◽

Gene Expression Patterns ◽

Postnatal Life ◽

Methylation Patterns

Pancreatic beta cells play a central role in regulating glucose homeostasis by secreting the hormone insulin. Failure of beta cells due to reduced function and mass and the resulting insulin insufficiency can drive the dysregulation of glycemic control, causing diabetes. Epigenetic regulation by DNA methylation is central to shaping the gene expression patterns that define the fully functional beta cell phenotype and regulate beta cell growth. Establishment of stage-specific DNA methylation guides beta cell differentiation during fetal development, while faithful restoration of these signatures during DNA replication ensures the maintenance of beta cell identity and function in postnatal life. Lineage-specific transcription factor networks interact with methylated DNA at specific genomic regions to enhance the regulatory specificity and ensure the stability of gene expression patterns. Recent genome-wide DNA methylation profiling studies comparing islets from diabetic and non-diabetic human subjects demonstrate the perturbation of beta cell DNA methylation patterns, corresponding to the dysregulation of gene expression associated with mature beta cell state in diabetes. This article will discuss the molecular underpinnings of shaping the islet DNA methylation landscape, its mechanistic role in the specification and maintenance of the functional beta cell phenotype, and its dysregulation in diabetes. We will also review recent advances in utilizing beta cell specific DNA methylation patterns for the development of biomarkers for diabetes, and targeting DNA methylation to develop translational approaches for supplementing the functional beta cell mass deficit in diabetes.

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Divergent neuronal DNA methylation patterns across human cortical development: Critical periods and a unique role of CpH methylation

10.1101/428391 ◽

2018 ◽

Cited By ~ 1

Author(s):

AJ Price ◽

L Collado-Torres ◽

NA Ivanov ◽

W Xia ◽

EE Burke ◽

...

Keyword(s):

Dna Methylation ◽

Developmental Trajectories ◽

Postnatal Life ◽

Critical Periods ◽

Neocortical Development ◽

Genome Wide ◽

Genome Bisulfite Sequencing ◽

Highly Correlated ◽

Methylation Patterns

AbstractWe have characterized the landscape of DNA methylation (DNAm) across the first two decades of human neocortical development in NeuN+ neurons using whole-genome bisulfite sequencing and compared them to non-neurons (primarily glia) and prenatal homogenate cortex. We show that DNAm changes more dramatically during the first five years of postnatal life than during the entire remaining period. We further refined global patterns of increasingly divergent neuronal CpG and CpH methylation (mCpG and mCpH) into six developmental trajectories and found that in contrast to genome-wide patterns, neighboring mCpG and mCpH levels within these regions were highly correlated. We then integrated paired RNA-seq data and identified direct regulation of hundreds of transcripts and their splicing events exclusively by mCpH levels, independently from mCpG levels, across this period. We finally explored the relationship between DNAm patterns and development of brain-related phenotypes and found enriched heritability for many phenotypes within DNAm features we identify.

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Prenatal Air Pollution Exposure and Placental DNA Methylation Changes: Implications on Fetal Development and Future Disease Susceptibility

Cells ◽

10.3390/cells10113025 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3025

Author(s):

Terisha Ghazi ◽

Pragalathan Naidoo ◽

Rajen N. Naidoo ◽

Anil A. Chuturgoon

Keyword(s):

Heavy Metals ◽

Dna Methylation ◽

Air Pollution ◽

Fetal Programming ◽

Fetal Development ◽

Disease Susceptibility ◽

Current Knowledge ◽

Later Life ◽

In Utero ◽

Methylation Patterns

The Developmental Origins of Health and Disease (DOHaD) concept postulates that in utero exposures influence fetal programming and health in later life. Throughout pregnancy, the placenta plays a central role in fetal programming; it regulates the in utero environment and acts as a gatekeeper for nutrient and waste exchange between the mother and the fetus. Maternal exposure to air pollution, including heavy metals, can reach the placenta, where they alter DNA methylation patterns, leading to changes in placental function and fetal reprogramming. This review explores the current knowledge on placental DNA methylation changes associated with prenatal air pollution (including heavy metals) exposure and highlights its effects on fetal development and disease susceptibility. Prenatal exposure to air pollution and heavy metals was associated with altered placental DNA methylation at the global and promoter regions of genes involved in biological processes such as energy metabolism, circadian rhythm, DNA repair, inflammation, cell differentiation, and organ development. The altered placental methylation of these genes was, in some studies, associated with adverse birth outcomes such as low birth weight, small for gestational age, and decreased head circumference. Moreover, few studies indicate that DNA methylation changes in the placenta were sex-specific, and infants born with altered placental DNA methylation patterns were predisposed to developing neurobehavioral abnormalities, cancer, and atopic dermatitis. These findings highlight the importance of more effective and stricter environmental and public health policies to reduce air pollution and protect human health.

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Examination of the dynamics of global DNA methylation pattern establishment during spermatogenesiss

Clinical & Investigative Medicine ◽

10.25011/cim.v30i4.2868 ◽

2007 ◽

Vol 30 (4) ◽

pp. 90

Author(s):

Kirsten Niles ◽

Sophie La Salle ◽

Christopher Oakes ◽

Jacquetta Trasler

Keyword(s):

Dna Methylation ◽

Germ Cell ◽

Germ Cells ◽

Epigenetic Modification ◽

Methylation Pattern ◽

Chromosome 9 ◽

Specific Gene ◽

Global Methylation ◽

Dna Methylation Pattern ◽

Methylation Patterns

Background: DNA methylation is an epigenetic modification involved in gene expression, genome stability, and genomic imprinting. In the male, methylation patterns are initially erased in primordial germ cells (PGCs) as they enter the gonadal ridge; methylation patterns are then acquired on CpG dinucleotides during gametogenesis. Correct pattern establishment is essential for normal spermatogenesis. To date, the characterization and timing of methylation pattern acquisition in PGCs has been described using a limited number of specific gene loci. This study aimed to describe DNA methylation pattern establishment dynamics during male gametogenesis through global methylation profiling techniques in a mouse model. Methods: Using a chromosome based approach, primers were designed for 24 regions spanning chromosome 9; intergenic, non-repeat, non-CpG island sequences were chosen for study based on previous evidence that these types of sequences are targets for testis-specific methylation events. The percent methylation was determined in each region by quantitative analysis of DNA methylation using real-time PCR (qAMP). The germ cell-specific pattern was determined by comparing methylation between spermatozoa and liver. To examine methylation in developing germ cells, spermatogonia from 2 day- and 6 day-old Oct4-GFP (green fluorescent protein) mice were isolated using fluorescence activated cell sorting. Results: As compared to liver, four loci were hypomethylated and five loci were hypermethylated in spermatozoa, supporting previous results indicating a unique methylation pattern in male germ cells. Only one region was hypomethylated and no regions were hypermethylated in day 6 spermatogonia as compared to mature spermatozoa, signifying that the bulk of DNA methylation is established prior to type A spermatogonia. The methylation in day 2 spermatogonia, germ cells that are just commencing mitosis, revealed differences of 15-20% compared to day 6 spermatogonia at five regions indicating that the most crucial phase of DNA methylation acquisition occurs prenatally. Conclusion: Together, these studies provide further evidence that germ cell methylation patterns differ from those in somatic tissues and suggest that much of methylation at intergenic sites is acquired during prenatal germ cell development. (Supported by CIHR)

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DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Communications Biology ◽

10.1038/s42003-020-01469-0 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Vanessa Lakis ◽

◽

Rita T. Lawlor ◽

Felicity Newell ◽

Ann-Marie Patch ◽

...

Keyword(s):

Dna Methylation ◽

Neuroendocrine Tumors ◽

Methylation Profile ◽

Pancreatic Neuroendocrine Tumors ◽

Wild Type ◽

Genomic Information ◽

Chromosome 11 ◽

Dna Methylation Profile ◽

Methylation Patterns ◽

Recurrent Patterns

AbstractHere we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.

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Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

Communications Biology ◽

10.1038/s42003-021-02179-x ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Todd R. Robeck ◽

Zhe Fei ◽

Ake T. Lu ◽

Amin Haghani ◽

Eve Jourdain ◽

...

Keyword(s):

Dna Methylation ◽

Age Estimation ◽

Species Conservation ◽

Genome Wide ◽

Epigenetic Aging ◽

Highly Correlated ◽

Methylation Patterns ◽

Cg Dinucleotides ◽

Free Ranging ◽

Unique Species

AbstractThe development of a precise blood or skin tissue DNA Epigenetic Aging Clock for Odontocete (OEAC) would solve current age estimation inaccuracies for wild odontocetes. Therefore, we determined genome-wide DNA methylation profiles using a custom array (HorvathMammalMethyl40) across skin and blood samples (n = 446) from known age animals representing nine odontocete species within 4 phylogenetic families to identify age associated CG dinucleotides (CpGs). The top CpGs were used to create a cross-validated OEAC clock which was highly correlated for individuals (r = 0.94) and for unique species (median r = 0.93). Finally, we applied the OEAC for estimating the age and sex of 22 wild Norwegian killer whales. DNA methylation patterns of age associated CpGs are highly conserved across odontocetes. These similarities allowed us to develop an odontocete epigenetic aging clock (OEAC) which can be used for species conservation efforts by provide a mechanism for estimating the age of free ranging odontocetes from either blood or skin samples.

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Aging-associated distinctive DNA methylation changes of LINE-1 retrotransposons in pure cell-free DNA from human blood

Scientific Reports ◽

10.1038/s41598-020-79126-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Wardah Mahmood ◽

Lars Erichsen ◽

Pauline Ott ◽

Wolfgang A. Schulz ◽

Johannes C. Fischer ◽

...

Keyword(s):

Dna Methylation ◽

Cell Free Dna ◽

The Past ◽

Free Dna ◽

Genome Wide ◽

Cancerous Cell ◽

Pure Cell ◽

Epigenetic Biomarker ◽

Methylation Patterns ◽

Cancerous Cells

AbstractLINE-1 hypomethylation of cell-free DNA has been described as an epigenetic biomarker of human aging. However, in the past, insufficient differentiation between cellular and cell-free DNA may have confounded analyses of genome-wide methylation levels in aging cells. Here we present a new methodological strategy to properly and unambiguously extract DNA methylation patterns of repetitive, as well as single genetic loci from pure cell-free DNA from peripheral blood. Since this nucleic acid fraction originates mainly in apoptotic, senescent and cancerous cells, this approach allows efficient analysis of aged and cancerous cell-specific DNA methylation patterns for diagnostic and prognostic purposes. Using this methodology, we observe a significant age-associated erosion of LINE-1 methylation in cfDNA suggesting that the threshold of hypomethylation sufficient for relevant LINE-1 activation and consequential harmful retrotransposition might be reached at higher age. We speculate that this process might contribute to making aging the main risk factor for many cancers.

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