Recent progress towards understanding the role of DNA methylation in human placental development

Epigenetic modifications, and particularly DNA methylation, have been studied in many tissues, both healthy and diseased, and across numerous developmental stages. The placenta is the only organ that has a transient life of 9 months and undergoes rapid growth and dynamic structural and functional changes across gestation. Additionally, the placenta is unique because although developing within the mother, its genome is identical to that of the foetus. Given these distinctive characteristics, it is not surprising that the epigenetic landscape affecting placental gene expression may be different to that in other healthy tissues. However, the role of epigenetic modifications, and particularly DNA methylation, in placental development remains largely unknown. Of particular interest is the fact that the placenta is the most hypomethylated human tissue and is characterized by the presence of large partially methylated domains (PMDs) containing silenced genes. Moreover, how and why the placenta is hypomethylated and what role DNA methylation plays in regulating placental gene expression across gestation are poorly understood. We review genome-wide DNA methylation studies in the human placenta and highlight that the different cell types that make up the placenta have very different DNA methylation profiles. Summarizing studies on DNA methylation in the placenta and its relationship with pregnancy complications are difficult due to the limited number of studies available for comparison. To understand the key steps in placental development and hence what may be perturbed in pregnancy complications requires large-scale genome-wide DNA methylation studies coupled with transcriptome analyses.

Download Full-text

DDR1 methylation is associated with bipolar disorder and the isoform expression and methylation of myelin genes

Epigenomics ◽

10.2217/epi-2021-0006 ◽

2021 ◽

Author(s):

Beatriz Garcia-Ruiz ◽

Manuel Castro de Moura ◽

Gerard Muntané ◽

Lourdes Martorell ◽

Elena Bosch ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Bipolar Disorder ◽

Mrna Expression ◽

Gene Expression Analysis ◽

Mrna Levels ◽

Healthy Controls ◽

Genome Wide ◽

Isoform Expression

Aim: To investigate DDR1 methylation in the brains of bipolar disorder (BD) patients and its association with DDR1 mRNA levels and comethylation with myelin genes. Materials & methods: Genome-wide profiling of DNA methylation (Infinium MethylationEPIC BeadChip) corrected for glial composition and DDR1 gene expression analysis in the occipital cortices of individuals with BD (n = 15) and healthy controls (n = 15) were conducted. Results: DDR1 5-methylcytosine levels were increased and directly associated with DDR1b mRNA expression in the brains of BD patients. We also observed that DDR1 was comethylated with a group of myelin genes. Conclusion: DDR1 is hypermethylated in BD brain tissue and is associated with isoform expression. Additionally, DDR1 comethylation with myelin genes supports the role of this receptor in myelination.

Download Full-text

Epigenetic mechanisms in sexual differentiation of the brain and behaviour

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0114 ◽

2016 ◽

Vol 371 (1688) ◽

pp. 20150114 ◽

Cited By ~ 34

Author(s):

Nancy G. Forger

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Sexual Differentiation ◽

Wide Distribution ◽

Epigenetic Modifications ◽

Epigenetic Mechanism ◽

Epigenetic Mechanisms ◽

Genome Wide ◽

The Brain

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

Download Full-text

DNA Methylation and Transcriptomic Features are Preserved Throughout Disease Recurrence and Chemoresistance in High Grade Serous Ovarian Cancers

10.21203/rs.3.rs-1214611/v1 ◽

2022 ◽

Author(s):

Nicole Gull ◽

Michell Jones ◽

Pei-Chen Peng ◽

Simon Coetzee ◽

Tiago Silva ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Bisulfite Sequencing ◽

Disease Recurrence ◽

High Grade ◽

Chemotherapy Treatment ◽

Recurrent Tumors ◽

Genome Wide ◽

Genome Bisulfite Sequencing

Abstract Background Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations. Results Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P=0.006) in these BRCA1/2 carriers. Conclusions These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC.

Download Full-text

Genome-wide DNA methylation analysis in multiple tissues in primary Sjögren's syndrome reveals regulatory effects at interferon-induced genes

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-208659 ◽

2016 ◽

Vol 75 (11) ◽

pp. 2029-2036 ◽

Cited By ~ 70

Author(s):

Juliana Imgenberg-Kreuz ◽

Johanna K Sandling ◽

Jonas Carlsson Almlöf ◽

Jessica Nordlund ◽

Linnea Signér ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Salivary Gland ◽

B Cells ◽

Whole Blood ◽

Minor Salivary Gland ◽

Genome Wide ◽

Induced Genes ◽

Regulatory Effects

ObjectivesIncreasing evidence suggests an epigenetic contribution to the pathogenesis of autoimmune diseases, including primary Sjögren's Syndrome (pSS). The aim of this study was to investigate the role of DNA methylation in pSS by analysing multiple tissues from patients and controls.MethodsGenome-wide DNA methylation profiles were generated using HumanMethylation450K BeadChips for whole blood, CD19+ B cells and minor salivary gland biopsies. Gene expression was analysed in CD19+ B cells by RNA-sequencing. Analysis of genetic regulatory effects on DNA methylation at known pSS risk loci was performed.ResultsWe identified prominent hypomethylation of interferon (IFN)-regulated genes in whole blood and CD19+ B cells, including at the genes MX1, IFI44L and PARP9, replicating previous reports in pSS, as well as identifying a large number of novel associations. Enrichment for genomic overlap with histone marks for enhancer and promoter regions was observed. We showed for the first time that hypomethylation of IFN-regulated genes in pSS B cells was associated with their increased expression. In minor salivary gland biopsies we observed hypomethylation of the IFN-induced gene OAS2. Pathway and disease analysis resulted in enrichment of antigen presentation, IFN signalling and lymphoproliferative disorders. Evidence for genetic control of methylation levels at known pSS risk loci was observed.ConclusionsOur study highlights the role of epigenetic regulation of IFN-induced genes in pSS where replication is needed for novel findings. The association with altered gene expression suggests a functional mechanism for differentially methylated CpG sites in pSS aetiology.

Download Full-text

Incorporation of DNA methylation into eQTL mapping in African Americans

10.1101/2020.08.05.238030 ◽

2020 ◽

Author(s):

Anmol Singh ◽

Yizhen Zhong ◽

Layan Nahlawi ◽

C. Sehwan Park ◽

Tanima De ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

African Americans ◽

Genetic Basis ◽

Critical Role ◽

Eqtl Analysis ◽

Biliary Cirrhosis ◽

Eqtl Mapping ◽

Genome Wide

Epigenetics is a reversible molecular mechanism that plays a critical role in many developmental, adaptive, and disease processes. DNA methylation has been shown to regulate gene expression and the advent of high throughput technologies has made genome-wide DNA methylation analysis possible. We investigated the effect of DNA methylation in eQTL mapping (methylation-adjusted eQTLs), by incorporating DNA methylation as a SNP-based covariate in eQTL mapping in African American derived hepatocytes. We found that the addition of DNA methylation uncovered new eQTLs and eGenes. Previously discovered eQTLs were significantly altered by the addition of DNA methylation data suggesting that methylation may modulate the association of SNPs to gene expression. We found that methylation-adjusted eQTLs which were less significant compared to PC-adjusted eQTLs were enriched in lipoprotein measurements (FDR = 0.0040), immune system disorders (FDR = 0.0042), and liver enzyme measurements (FDR = 0.047), suggesting a role of DNA methylation in regulating the genetic basis of these phenotypes. Our methylation-adjusted eQTL analysis also uncovered novel SNP-gene pairs. For example, our study found the SNP, rs11546996, was associated to PNKP. In a previous GWAS, this SNP was associated with primary biliary cirrhosis although the causal gene was thought to be SPIB. Our methylation-adjusted method potentially adds new understanding to the genetic basis of complex diseases that disproportionally affect African Americans.

Download Full-text

The role of epigenetic modifications in plant responses to stress

Botanica Serbica ◽

10.2298/botserb2101003l ◽

2021 ◽

Vol 45 (1) ◽

pp. 3-12

Author(s):

Xuefeng Lu ◽

Tae Hyun

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Current Knowledge ◽

Epigenetic Modifications ◽

Plant Responses ◽

Daughter Cells ◽

Non Coding Rnas ◽

Covalent Modifications ◽

Mitosis And Meiosis

Epigenetics is the study of hereditary changes in gene expression under the premise that the nucleotide sequence is not changed. Such hereditary changes mainly involve DNA methylation, histone modification, and chromatin remodeling. These covalent modifications play indispensable roles in regulating gene expression; DNA replication, recombination, and repair; and cell differentiation. Epigenetic modifications can be partially inherited by daughter cells during mitosis and meiosis and influenced by external factors, such as environmental stresses and supply deficits. In this review, we summarize the current knowledge regarding epigenetic factors, such as DNA methylation, histone acetylation, and regulation by non-coding RNAs, in the development and stress response of plants.

Download Full-text

Gene expression imputation across multiple brain regions reveals schizophrenia risk throughout development

10.1101/222596 ◽

2017 ◽

Cited By ~ 7

Author(s):

Laura M. Huckins ◽

Amanda Dobbyn ◽

Douglas M. Ruderfer ◽

Gabriel Hoffman ◽

Weiqing Wang ◽

...

Keyword(s):

Gene Expression ◽

Large Scale ◽

Expression Patterns ◽

Brain Regions ◽

Developmental Expression ◽

Genotype Data ◽

Genome Wide ◽

Hexosaminidase A ◽

Gene Expression Levels

AbstractTranscriptomic imputation approaches offer an opportunity to test associations between disease and gene expression in otherwise inaccessible tissues, such as brain, by combining eQTL reference panels with large-scale genotype data. These genic associations could elucidate signals in complex GWAS loci and may disentangle the role of different tissues in disease development. Here, we use the largest eQTL reference panel for the dorso-lateral pre-frontal cortex (DLPFC), collected by the CommonMind Consortium, to create a set of gene expression predictors and demonstrate their utility. We applied these predictors to 40,299 schizophrenia cases and 65,264 matched controls, constituting the largest transcriptomic imputation study of schizophrenia to date. We also computed predicted gene expression levels for 12 additional brain regions, using publicly available predictor models from GTEx. We identified 413 genic associations across 13 brain regions. Stepwise conditioning across the genes and tissues identified 71 associated genes (67 outside the MHC), with the majority of associations found in the DLPFC, and of which 14/67 genes did not fall within previously genome-wide significant loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple pathways associated with porphyric disorders. We investigated developmental expression patterns for all 67 non-MHC associated genes using BRAINSPAN, and identified groups of genes expressed specifically pre-natally or post-natally.

Download Full-text

X chromosome-dependent disruption of placental regulatory networks in hybrid dwarf hamsters

Genetics ◽

10.1093/genetics/iyab043 ◽

2021 ◽

Author(s):

Thomas D Brekke ◽

Emily C Moore ◽

Shane C Campbell-Staton ◽

Colin M Callahan ◽

Zachary A Cheviron ◽

...

Keyword(s):

Gene Expression ◽

X Chromosome ◽

Regulatory Networks ◽

Mammalian Species ◽

Strongly Correlated ◽

Placental Development ◽

Substitution Lines ◽

Genome Wide ◽

Highly Sensitive ◽

First And Second Generation

AbstractEmbryonic development in mammals is highly sensitive to changes in gene expression within the placenta. The placenta is also highly enriched for genes showing parent-of-origin or imprinted expression, which is predicted to evolve rapidly in response to parental conflict. However, little is known about the evolution of placental gene expression, or if divergence of placental gene expression plays an important role in mammalian speciation. We used crosses between two species of dwarf hamsters (Phodopus sungorus and Phodopus campbelli) to examine the genetic and regulatory underpinnings of severe placental overgrowth in their hybrids. Using quantitative genetic mapping and mitochondrial substitution lines, we show that overgrowth of hybrid placentas was primarily caused by genetic differences on the maternally inherited P. sungorus X chromosome. Mitochondrial interactions did not contribute to abnormal hybrid placental development, and there was only weak correspondence between placental disruption and embryonic growth. Genome-wide analyses of placental transcriptomes from the parental species and first- and second-generation hybrids revealed a central group of co-expressed X-linked and autosomal genes that were highly enriched for maternally biased expression. Expression of this gene network was strongly correlated with placental size and showed widespread misexpression dependent on epistatic interactions with X-linked hybrid incompatibilities. Collectively, our results indicate that the X chromosome is likely to play a prominent role in the evolution of placental gene expression and the accumulation of hybrid developmental barriers between mammalian species.

Download Full-text

Genome-Wide Identification of Soybean ABC Transporters Relate to Aluminum Toxicity

International Journal of Molecular Sciences ◽

10.3390/ijms22126556 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6556

Author(s):

Junjun Huang ◽

Xiaoyu Li ◽

Xin Chen ◽

Yaru Guo ◽

Weihong Liang ◽

...

Keyword(s):

Gene Expression ◽

Abc Transporters ◽

Developmental Stages ◽

Aluminum Toxicity ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Purifying Selection ◽

Biotic Stresses ◽

Genome Wide ◽

New Germplasm

ATP-binding cassette (ABC) transporter proteins are a gene super-family in plants and play vital roles in growth, development, and response to abiotic and biotic stresses. The ABC transporters have been identified in crop plants such as rice and buckwheat, but little is known about them in soybean. Soybean is an important oil crop and is one of the five major crops in the world. In this study, 255 ABC genes that putatively encode ABC transporters were identified from soybean through bioinformatics and then categorized into eight subfamilies, including 7 ABCAs, 52 ABCBs, 48 ABCCs, 5 ABCDs, 1 ABCEs, 10 ABCFs, 111 ABCGs, and 21 ABCIs. Their phylogenetic relationships, gene structure, and gene expression profiles were characterized. Segmental duplication was the main reason for the expansion of the GmABC genes. Ka/Ks analysis suggested that intense purifying selection was accompanied by the evolution of GmABC genes. The genome-wide collinearity of soybean with other species showed that GmABCs were relatively conserved and that collinear ABCs between species may have originated from the same ancestor. Gene expression analysis of GmABCs revealed the distinct expression pattern in different tissues and diverse developmental stages. The candidate genes GmABCB23, GmABCB25, GmABCB48, GmABCB52, GmABCI1, GmABCI5, and GmABCI13 were responsive to Al toxicity. This work on the GmABC gene family provides useful information for future studies on ABC transporters in soybean and potential targets for the cultivation of new germplasm resources of aluminum-tolerant soybean.

Download Full-text