scholarly journals Divergent neuronal DNA methylation patterns across human cortical development reveal critical periods and a unique role of CpH methylation

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Amanda J. Price ◽  
Leonardo Collado-Torres ◽  
Nikolay A. Ivanov ◽  
Wei Xia ◽  
Emily E. Burke ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Developmental Trajectories ◽  
Cortical Development ◽  
Postnatal Life ◽  
Critical Periods ◽  
Neuropsychiatric Diseases ◽  
Genome Bisulfite Sequencing ◽  
Highly Correlated ◽  
Genomic Regions ◽  
The Relationship

Abstract Background DNA methylation (DNAm) is a critical regulator of both development and cellular identity and shows unique patterns in neurons. To better characterize maturational changes in DNAm patterns in these cells, we profile the DNAm landscape at single-base resolution across the first two decades of human neocortical development in NeuN+ neurons using whole-genome bisulfite sequencing and compare them to non-neurons (primarily glia) and prenatal homogenate cortex. Results We show that DNAm changes more dramatically during the first 5 years of postnatal life than during the entire remaining period. We further refine global patterns of increasingly divergent neuronal CpG and CpH methylation (mCpG and mCpH) into six developmental trajectories and find that in contrast to genome-wide patterns, neighboring mCpG and mCpH levels within these regions are highly correlated. We integrate paired RNA-seq data and identify putative regulation of hundreds of transcripts and their splicing events exclusively by mCpH levels, independently from mCpG levels, across this period. We finally explore the relationship between DNAm patterns and development of brain-related phenotypes and find enriched heritability for many phenotypes within identified DNAm features. Conclusions By profiling DNAm changes in NeuN-sorted neurons over the span of human cortical development, we identify novel, dynamic regions of DNAm that would be masked in homogenate DNAm data; expand on the relationship between CpG methylation, CpH methylation, and gene expression; and find enrichment particularly for neuropsychiatric diseases in genomic regions with cell type-specific, developmentally dynamic DNAm patterns.

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

2018 ◽  
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.

scholarly journals Identification of polymorphic and off-target probe binding sites on the Illumina Infinium MethylationEPIC BeadChip

2016 ◽  
Author(s):  
Daniel L. McCartney ◽  
Rosie M. Walker ◽  
Stewart W. Morris ◽  
Andrew M. McIntosh ◽  
David J. Porteous ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genome Wide ◽  
Wide Range ◽  
Control Procedures ◽  
Target Probe ◽  
Genomic Regions ◽  
Array Performance ◽  
The Relationship ◽  
Inexpensive Technique ◽  
Methylation Profiling

AbstractGenome-wide analysis of DNA methylation has now become a relatively inexpensive technique thanks to array-based methylation profiling technologies. The recently developed Illumina Infinium MethylationEPIC BeadChip interrogates methylation at over 850,000 sites across the human genome, covering 99% of RefSeq genes. This array supersedes the widely used Infinium HumanMethylation450 BeadChip, which has permitted insights into the relationship between DNA methylation and a wide range of conditions and traits. Previous research has identified issues with certain probes on both the HumanMethylation450 BeadChip and its predecessor, the Infinium HumanMethylation27 BeadChip, which were predicted to affect array performance. These issues concerned probe-binding specificity and the presence of polymorphisms at target sites. Using in silico methods, we have identified probes on the Infinium MethylationEPIC BeadChip that are predicted to (i) measure methylation at polymorphic sites and (ii) hybridise to multiple genomic regions. We intend these resources to be used for quality control procedures when analysing data derived from this platform.

scholarly journals Temporal proteomic profiling of postnatal human cortical development

2017 ◽  
Author(s):  
Michael S. Breen ◽  
Sureyya Ozcan ◽  
Jordan M. Ramsey ◽  
Zichen Wang ◽  
Avi Ma’ayan ◽  
...  
Keyword(s):  
Protein Expression ◽  
Developmental Trajectories ◽  
Expression Profiles ◽  
Cortical Development ◽  
Postnatal Life ◽  
Regulation Of Transcription ◽  
Transcriptome Data ◽  
Proteomic Profiling ◽  
Data Resource ◽  
Age Related

AbstractHealthy cortical development depends on precise regulation of transcription and translation. However, the dynamics of how proteins are expressed, function and interact across postnatal human cortical development remain poorly understood. We surveyed the proteomic landscape of 69 dorsolateral prefrontal cortex samples across seven stages of postnatal life and integrated these data with paired transcriptome data. We detected 911 proteins by liquid chromatography-mass spectrometry, and 83 were significantly associated with postnatal age (FDR p < 0.05). Network analysis identified three modules of co-regulated proteins correlated with age, including two modules with increasing expression involved in gliogenesis and NADH-metabolism and one neurogenesis-related module with decreasing expression throughout development. Integration with paired transcriptome data revealed that these age-related protein modules overlapped with RNA modules and displayed collinear developmental trajectories. Importantly, RNA expression profiles that are dynamically regulated throughout cortical development display tighter correlations with their respective translated protein expression compared to those RNA profiles that are not. Moreover, the correspondence between RNA and protein expression significantly decreases as a function of cortical aging, especially for genes involved in myelination and cytoskeleton organization. Finally, we used this data resource to elucidate the functional impact of genetic risk loci for intellectual disability, converging on gliogenesis, myelination and ATP-metabolism modules in the proteome and transcriptome. We share all data in an interactive, searchable companion website. Collectively, our findings reveal dynamic aspects of protein regulation and provide new insights into brain development, maturation and disease.

scholarly journals Pan-Cancer Analysis of DNA Methylation Identifies Genes and Biological Functions Associated with Overall Survival

2021 ◽  
Author(s):  
Romola Grace Cavet ◽  
Peng Yue ◽  
Guy Lawrence Cavet
Keyword(s):  
Dna Methylation ◽  
Overall Survival ◽  
Cancer Biology ◽  
Gene Clusters ◽  
The Cancer Genome Atlas ◽  
Biological Functions ◽  
Cancer Types ◽  
Genomic Regions ◽  
The Relationship ◽  
Pan Cancer

DNA methylation influences gene expression and is altered in many cancers, but the relationship between DNA methylation and cancer outcomes is not yet fully understood. If methylation of specific genes is associated with better or worse outcomes, it could implicate genes in driving cancer and suggest therapeutic strategies. To advance our understanding of DNA methylation in cancer biology, we conducted a pan-cancer analysis of the relationship between methylation and overall survival. Using data on 28 tumor types from The Cancer Genome Atlas (TCGA), we identified genes and genomic regions whose methylation was recurrently associated with survival across multiple cancer types. While global DNA methylation levels are associated with outcome in some cancers, we found that the gene-specific associations were largely independent of these global effects. Genes with recurrent associations across cancer types were enriched for certain biological functions, such as immunity and cell-cell adhesion. While these recurrently associated genes were found throughout the genome, they were enriched in certain genomic regions, which may further implicate certain gene families and gene clusters in affecting survival. By finding common features across cancer types, our results link DNA methylation to patient outcomes, identify biological mechanisms that could explain survival differences, and support the potential value of treatments that modulate the methylation of tumor DNA.

scholarly journals Simultaneous profiling of DNA methylation and chromatin architecture in mixed populations and in single cells

2018 ◽  
Author(s):  
Guoqiang Li ◽  
Yaping Liu ◽  
Yanxiao Zhang ◽  
Rongxin Fang ◽  
Manolis Kellis ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Cells ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Specific Gene ◽  
Mixed Cell ◽  
Chromosome Conformation ◽  
Chromatin Architecture ◽  
Genome Bisulfite Sequencing ◽  
Genomic Regions

AbstractDynamic DNA methylation and three-dimensional chromatin architecture compose a major portion of a cell’s epigenome and play an essential role in tissue specific gene expression programs. Currently, DNA methylation and chromatin organization are generally profiled in separate assays. Here, we report Methyl-HiC, a method combining in situ Hi-C and whole genome bisulfite sequencing (WGBS) to simultaneously capture chromosome conformation and DNA methylome in a single assay. Methyl-HiC analysis of mouse embryonic stem cells reveals coordinated DNA methylation between distant yet spatially proximal genomic regions. Extension of Methyl-HiC to single cells further enables delineation of the heterogeneity of both chromosomal conformation and DNA methylation in a mixed cell population, and uncovers increased dynamics of chromatin contacts and decreased stochasticity in DNA methylation in genomic regions that replicate early during cell cycle.

scholarly journals Analysis of genome DNA methylation at inherited coat-color dilutions of Rex Rabbits

2020 ◽  
Author(s):  
Yang Chen ◽  
Shuaishuai Hu ◽  
Ming Liu ◽  
Bohao Zhao ◽  
Naisu Yang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Coat Color ◽  
Hair Follicles ◽  
Bisulfite Treatment ◽  
Genome Wide ◽  
Genome Bisulfite Sequencing ◽  
Genetic Mechanisms ◽  
Different Color ◽  
Rex Rabbit ◽  
The Relationship

Abstract Background Dilution of color in rabbits is associated with many different genetic mechanisms that form different color groups. A number of previous studies have revealed potential regulatory mechanisms by which epigenetics regulate pigmentation. However, the genome-wide DNA methylation involved in animal coat-color dilution remains unknown.Results We compared genome-wide DNA methylation profiles in Rex rabbit hair follicles in a Chinchilla group (Ch) and a diluted Chinchilla group (DCh) through whole-genome bisulfite sequencing (WGBS). Approximately 3.5% of the cytosine sites were methylated in both groups, of which the CG methylation type was in greatest abundance. In total, we identified 126,405 differentially methylated regions (DMRs) between the two groups, corresponding to 11,459 DMR-associated genes (DMGs). Gene ontogeny (GO) and KEGG pathway analysis revealed that these DMGs were principally involved in developmental pigmentation and Wnt signaling pathways. In addition, 2 DMRs were randomly selected to verify that the WGBS data were reliable using bisulfite treatment (BSP), and 7 DMGs were analyzed to establish the relationship between the level of DNA methylation and mRNA expression using qRT-PCR.Conclusion These findings provide evidence that there is an association between inherited color dilution and DNA methylation alterations in hair follicles, greatly contributing to our understanding of the epigenetic regulation of rabbit pigmentation.

Sex-biased DNA methylation in papillary thyroid cancer

2021 ◽  
Vol 15 (2) ◽  
pp. 109-120
Author(s):  
Rui Han ◽  
Wei Sun ◽  
Jiapeng Huang ◽  
Liang Shao ◽  
Hao Zhang
Keyword(s):  
Dna Methylation ◽  
Thyroid Cancer ◽  
Papillary Thyroid Cancer ◽  
Immune Cell ◽  
Gene Promoter ◽  
Papillary Thyroid ◽  
Promoter Regions ◽  
Genomic Regions ◽  
Methylation Patterns ◽  
The Relationship

Background: Women have a higher risk of developing papillary thyroid cancer (PTC) than men. DNA methylation is known to differ between men and women. Materials & methods: Using the human methylation 450 BeadChip and RNA-sequence, we profiled the genome-wide DNA methylation patterns of papillary thyroid carcinoma patients and para-carcinoma tissue. Results: We first identified 398 different expression genes (DEGs) between males and females PTC. Then we analyzed the relationship between differentially methylated positions (DMPs) and DEGs at gene promoter regions and identified 39 genes and explored DMP-DEGs’ correlation with immune cell infiltration and tumor purity. We also analyzed the relationship between genomic regions and enhancers. Conclusion: Our study identified 39 DMP-DEGs providing some new insights into the mechanisms of methylation-mediated gender differences in PTC.

scholarly journals Predicting Methylation from Sequence and Gene Expression Using Deep Learning with Attention

2018 ◽  
Author(s):  
Alona Levy-Jurgenson ◽  
Xavier Tekpli ◽  
Vessela N. Kristensen ◽  
Zohar Yakhini
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Deep Learning ◽  
Methylation Status ◽  
Sequence Information ◽  
Expression Data ◽  
Living Organisms ◽  
Genomic Regions ◽  
The Relationship ◽  
Methylation Activity

AbstractDNA methylation has been extensively linked to alterations in gene expression, playing a key role in the manifestation of multiple diseases, most notably cancer. For this reason, researchers have long been measuring DNA methylation in living organisms. The relationship between methylation and expression, and between methylation in different genomic regions is of great theoretical interest from a molecular biology perspective. Therefore, several models have been suggested to support the prediction of methylation status in samples. These models, however, have two main limitations: (a) they heavily rely on partially measured methylation levels as input, somewhat defeating the object as one is required to collect measurements from the sample of interest before applying the model; and (b) they are largely based on human mediated feature engineering, thus preventing the model from unveiling its own representations. To address these limitations we used deep learning, with an attention mechanism, to produce a general model that predicts DNA methylation for a given sample in any CpG position based solely on the sample's gene expression profile and the sequence surrounding the CpG.We show that our model is capable of generalizing to a completely separate test set of CpG positions and subjects. Depending on gene-CpG proximity conditions, our model can attain a Spearman correlation of up to 0.8 and MAE of 0.14 for thousands of CpG sites in the test data. We also identify and analyze several motifs and genes that our model suggests may be linked to methylation activity, such as Nodal and Hand1. Moreover, our approach, and most notably the use of attention mechanisms, offers a novel framework with which to extract valuable insights from gene expression data when combined with sequence information.The code and trained models are available at:https://github.com/YakhiniGroup/Methylation

scholarly journals Global hypermethylation of intestinal epithelial cells is a hallmark feature of neonatal surgical necrotizing enterocolitis

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Misty Good ◽  
Tianjiao Chu ◽  
Patricia Shaw ◽  
Lora McClain ◽  
Austin Chamberlain ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Epithelial Cell ◽  
Necrotizing Enterocolitis ◽  
Regulation Of Gene Expression ◽  
Intestinal Epithelial ◽  
Genome Bisulfite Sequencing ◽  
Transcriptional Changes ◽  
Considerable Impact ◽  
Genomic Regions

Abstract Background Necrotizing enterocolitis (NEC) remains one of the overall leading causes of death in premature infants, and the pathogenesis is unpredictable and not well characterized. The aim of our study was to determine the molecular phenotype of NEC via transcriptomic and epithelial cell-specific epigenomic analysis, with a specific focus on DNA methylation. Methods Using laser capture microdissection, epithelial cell-specific methylation signatures were characterized by whole-genome bisulfite sequencing of ileal and colonic samples at the time of surgery for NEC and after NEC had healed at reanastomosis (n = 40). RNA sequencing was also performed to determine the transcriptomic profile of these samples, and a comparison was made to the methylome data. Results We found that surgical NEC has a considerable impact on the epigenome by broadly increasing DNA methylation levels, although these effects are less pronounced in genomic regions associated with the regulation of gene expression. Furthermore, NEC-related DNA methylation signatures were influenced by tissue of origin, with significant differences being noted between colon and ileum. We also identified numerous transcriptional changes in NEC and clear associations between gene expression and DNA methylation. Conclusions We have defined the intestinal epigenomic and transcriptomic signatures during surgical NEC, which will advance our understanding of disease pathogenesis and may enable the development of novel precision medicine approaches for NEC prediction, diagnosis and phenotyping.

Do Extra-Platelet Sources Contribute to the Plasma Level of Thrombospondin?

1988 ◽  
Vol 59 (02) ◽  
pp. 273-276 ◽  
Author(s):  
J Dawes ◽  
D A Pratt ◽  
M S Dewar ◽  
F E Preston
Keyword(s):  
Platelet Count ◽  
Background Concentration ◽  
Serum Concentrations ◽  
Bone Marrow Depression ◽  
Serial Sampling ◽  
Control Serum ◽  
Platelet Release ◽  
Highly Correlated ◽  
The Relationship

SummaryThrombospondin, a trimeric glycoprotein contained in the platelet α-granules, has been proposed as a marker of in vivo platelet activation. However, it is also synthesised by a range of other cells. The extraplatelet contribution to plasma levels of thrombospondin was therefore estimated by investigating the relationship between plasma thrombospondin levels and platelet count in samples from profoundly thrombocytopenic patients with marrow hypoplasia, using the platelet-specific α-granule protein β-thromboglobulin as control. Serum concentrations of both proteins were highly correlated with platelet count, but while plasma β-thromboglobulin levels and platelet count also correlated, there was no relationship between the number of platelets and thrombospondin concentrations in plasma. Serial sampling of patients recovering from bone marrow depression indicated that the plasma thrombospondin contributed by platelets is superimposed on a background concentration of at least 50 ng/ml probably derived from a non-platelet source, and plasma thrombospondin levels do not simply reflect platelet release.

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