scholarly journals Identification of differentially methylated cell-types in Epigenome-Wide Association Studies

2018 ◽  
Author(s):  
Shijie C Zheng ◽  
Charles E. Breeze ◽  
Stephan Beck ◽  
Andrew E. Teschendorff
Keyword(s):  
Dna Methylation ◽  
Association Studies ◽  
Cell Types ◽  
Differential Methylation ◽  
Specific Cell ◽  
Cell Type ◽  
Specific Cell Type ◽  
Current State ◽  
Buccal Swabs ◽  
Epithelial Compartment

An outstanding challenge of Epigenome-Wide Association Studies (EWAS) performed in complex tissues is the identification of the specific cell-type(s) responsible for the observed differential DNA methylation. Here, we present a novel statistical algorithm, called CellDMC, which is able to identify not only differentially methylated positions, but also the specific cell-type(s) driving the differential methylation. We provide extensive validation of CellDMC on in-silico mixtures of DNA methylation data generated with different technologies, as well as on real mixtures from epigenome-wide-association and cancer epigenome studies. We demonstrate how CellDMC can achieve over 90% sensitivity and specificity in scenarios where current state-of-the-art methods fail to identify differential methylation. By applying CellDMC to a smoking EWAS performed in buccal swabs, we identify differentially methylated positions occurring in the epithelial compartment, which we validate in smoking-related lung cancer. CellDMC may help towards the identification of causal DNA methylation alterations in disease.

scholarly journals Calling differential DNA methylation at cell-type resolution: an objective status-quo

2019 ◽  
Author(s):  
Han Jing ◽  
Shijie C. Zheng ◽  
Charles E. Breeze ◽  
Stephan Beck ◽  
Andrew E. Teschendorff
Keyword(s):  
Dna Methylation ◽  
Association Studies ◽  
Cell Types ◽  
Status Quo ◽  
Specific Cell ◽  
Cell Type ◽  
Causal Pathways ◽  
Key Issues ◽  
Cell Type Specific ◽  
Different Cell Types

AbstractDue to cost and logistical reasons, Epigenome-Wide-Association Studies (EWAS) are normally performed in complex tissues, resulting in average DNA methylation profiles over potentially many different cell-types, which can obscure important cell-type specific associations with disease. Identifying the specific cell-types that are altered is a key hurdle for elucidating causal pathways to disease, and consequently statistical algorithms have recently emerged that aim to address this challenge. Comparisons between these algorithms are of great interest, yet here we find that the main comparative study so far was substantially biased and potentially misleading. By using this study as an example, we highlight some of the key issues that need to be considered to ensure that future assessments between methods are more objective.

scholarly journals Mos in the Oocyte: How to Use MAPK Independently of Growth Factors and Transcription to Control Meiotic Divisions

2011 ◽  
Vol 2011 ◽  
pp. 1-15 ◽  
Author(s):  
Aude Dupré ◽  
Olivier Haccard ◽  
Catherine Jessus
Keyword(s):  
Growth Factors ◽  
Transcriptional Activation ◽  
Biological Activities ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Mitogen Activated Protein Kinase ◽  
Specific Cell ◽  
Cell Type ◽  
Specific Cell Type ◽  
Mitogen Activated Protein

In many cell types, the mitogen-activated protein kinase (MAPK) also named extracellular signal-regulated kinase (ERK) is activated in response to a variety of extracellular growth factor-receptor interactions and leads to the transcriptional activation of immediate early genes, hereby influencing a number of tissue-specific biological activities, as cell proliferation, survival and differentiation. In one specific cell type however, the female germ cell, MAPK does not follow this canonical scheme. In oocytes, MAPK is activated independently of growth factors and tyrosine kinase receptors, acts independently of transcriptional regulation, plays a crucial role in controlling meiotic divisions, and is under the control of a peculiar upstream regulator, the kinase Mos. Mos was originally identified as the transforming gene of Moloney murine sarcoma virus and its cellular homologue was the first proto-oncogene to be molecularly cloned. What could be the specific roles of Mos that render it necessary for meiosis? Which unique functions could explain the evolutionary cost to have selected one gene to only serve for few hours in one very specific cell type? This review discusses the original features of MAPK activation by Mos and the roles of this module in oocytes.

scholarly journals DNA Methylation Profiles of Purified Cell Types in Bronchoalveolar Lavage: Applications for Mixed Cell Paediatric Pulmonary Studies

2021 ◽  
Vol 12 ◽  
Author(s):  
Shivanthan Shanthikumar ◽  
Melanie R. Neeland ◽  
Richard Saffery ◽  
Sarath C. Ranganathan ◽  
Alicia Oshlack ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bronchoalveolar Lavage ◽  
Association Studies ◽  
Cell Types ◽  
Alveolar Epithelial Cells ◽  
Cell Type ◽  
Mixed Cell ◽  
Alveolar Epithelial ◽  
Cell Type Composition ◽  
Type Composition

In epigenome-wide association studies analysing DNA methylation from samples containing multiple cell types, it is essential to adjust the analysis for cell type composition. One well established strategy for achieving this is reference-based cell type deconvolution, which relies on knowledge of the DNA methylation profiles of purified constituent cell types. These are then used to estimate the cell type proportions of each sample, which can then be incorporated to adjust the association analysis. Bronchoalveolar lavage is commonly used to sample the lung in clinical practice and contains a mixture of different cell types that can vary in proportion across samples, affecting the overall methylation profile. A current barrier to the use of bronchoalveolar lavage in DNA methylation-based research is the lack of reference DNA methylation profiles for each of the constituent cell types, thus making reference-based cell composition estimation difficult. Herein, we use bronchoalveolar lavage samples collected from children with cystic fibrosis to define DNA methylation profiles for the four most common and clinically relevant cell types: alveolar macrophages, granulocytes, lymphocytes and alveolar epithelial cells. We then demonstrate the use of these methylation profiles in conjunction with an established reference-based methylation deconvolution method to estimate the cell type composition of two different tissue types; a publicly available dataset derived from artificial blood-based cell mixtures and further bronchoalveolar lavage samples. The reference DNA methylation profiles developed in this work can be used for future reference-based cell type composition estimation of bronchoalveolar lavage. This will facilitate the use of this tissue in studies examining the role of DNA methylation in lung health and disease.

scholarly journals Inference of cell-type specific imprinted regulatory elements and genes during human neuronal differentiation

2021 ◽  
Author(s):  
Dan Liang ◽  
Nil Aygün ◽  
Nana Matoba ◽  
Folami Ideraabdullah ◽  
Michael I Love ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neural Progenitor Cells ◽  
Association Studies ◽  
Cpg Islands ◽  
Uniparental Disomy ◽  
Cell Types ◽  
Regulatory Elements ◽  
Imprinted Genes ◽  
Specific Cell ◽  
Cell Type

Genomic imprinting results in gene expression biased by parental chromosome of origin and occurs in genes with important roles during human brain development. However, the cell-type and temporal specificity of imprinting during human neurogenesis is generally unknown. By detecting within-donor allelic biases in chromatin accessibility and gene expression that are unrelated to cross-donor genotype, we inferred imprinting in both primary human neural progenitor cells (phNPCs) and their differentiated neuronal progeny from up to 85 donors. We identified 43/20 putatively imprinted regulatory elements (IREs) in neurons/progenitors, and 133/79 putatively imprinted genes in neurons/progenitors. Though 10 IREs and 42 genes were shared between neurons and progenitors, most imprinting was only detected within specific cell types. In addition to well-known imprinted genes and their promoters, we inferred novel IREs and imprinted genes. We found IREs overlapped with CpG islands more than non-imprinted regulatory elements. Consistent with DNA methylation-based regulation of imprinted expression, some putatively imprinted regulatory elements also overlapped with differentially methylated regions on the maternal germline. Finally, we identified a progenitor-specific putatively imprinted gene overlap with copy number variation that is associated with uniparental disomy-like phenotypes. Our results can therefore be useful in interpreting the function of variants identified in future parent-of-origin association studies.

Cystic fibrosis affects specific cell type in sweat gland secretory coil

1997 ◽  
Vol 273 (2) ◽  
pp. C426-C433 ◽  
Author(s):  
M. M. Reddy ◽  
C. L. Bell ◽  
P. M. Quinton
Keyword(s):  
Cystic Fibrosis ◽  
Membrane Potential ◽  
Cell Membrane ◽  
Sweat Gland ◽  
Cell Types ◽  
Specific Cell ◽  
Cell Type ◽  
Specific Cell Type ◽  
Secretory Coil ◽  
Cholinergic Response

The sweat gland has three distinct cell types: a myoepithelial (ME) cell, a beta-adrenergic-insensitive (beta-I) cell, and a beta-adrenergic-sensitive (beta-S) cell. Using intracellular microelectrodes, we sought to functionally identify the specific cell type(s) affected in cystic fibrosis (CF). We found that in CF secretory coils 1) the ME calls are unaffected, as indicated by normal cell membrane potentials and spontaneous and cholinergically induced depolarizing potentials, 2) the beta-I cells showed normal physiological properties, including a relatively smaller cell membrane potential (approx -25 mV) and a Ba(2+)-inhibitable cholinergic response, and, in contrast, 3) the beta-S cell is abnormal, as shown by the lack of a beta-adrenergically activated cystic fibrosis transmembrane conductance regulator (CFTR) Cl- conductance (GCl). Lack of CFTR GCl in this cell type does not affect either the magnitude of cell membrane potential (approx -56 mV) or the relative cell membrane GCl or the cholinergic response, as compared with that of normal beta-S cells. We conclude that, of the three cell types in secretory coil, only the beta-S cell is specifically affected in the CF secretory tissue of the human sweat gland.

scholarly journals Cell-Specific DNA Methylation Signatures in Asthma

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 932 ◽  
Author(s):  
Andrée-Anne Hudon Thibeault ◽  
Catherine Laprise
Keyword(s):  
Dna Methylation ◽  
Mononuclear Cells ◽  
Association Studies ◽  
Complex Trait ◽  
Cell Types ◽  
Genome Wide Association Studies ◽  
Cell Type ◽  
Global Status ◽  
A Minor

Asthma is a complex trait, often associated with atopy. The genetic contribution has been evidenced by familial occurrence. Genome-wide association studies allowed for associating numerous genes with asthma, as well as identifying new loci that have a minor contribution to its phenotype. Considering the role of environmental exposure on asthma development, an increasing amount of literature has been published on epigenetic modifications associated with this pathology and especially on DNA methylation, in an attempt to better understand its missing heritability. These studies have been conducted in different tissues, but mainly in blood or its peripheral mononuclear cells. However, there is growing evidence that epigenetic changes that occur in one cell type cannot be directly translated into another one. In this review, we compare alterations in DNA methylation from different cells of the immune system and of the respiratory tract. The cell types in which data are obtained influences the global status of alteration of DNA methylation in asthmatic individuals compared to control (an increased or a decreased DNA methylation). Given that several genes were cell-type-specific, there is a great need for comparative studies on DNA methylation from different cells, but from the same individuals in order to better understand the role of epigenetics in asthma pathophysiology.

scholarly journals Caregiver maltreatment causes altered neuronal DNA methylation in female rodents

2017 ◽  
Vol 29 (2) ◽  
pp. 477-489 ◽  
Author(s):  
Jennifer Blaze ◽  
Tania L. Roth
Keyword(s):  
Dna Methylation ◽  
Prefrontal Cortex ◽  
Life Stress ◽  
Early Life ◽  
Cell Types ◽  
Specific Cell ◽  
Cell Type ◽  
Adult Rats ◽  
Methylation Of Dna ◽  
And Behavior

AbstractNegative experiences with a caregiver during infancy can result in long-term changes in brain function and behavior, but underlying mechanisms are not well understood. It is our central hypothesis that brain and behavior changes are conferred by early childhood adversity through epigenetic changes involving DNA methylation. Using a rodent model of early-life caregiver maltreatment (involving exposure to an adverse caregiving environment for postnatal days 1–7), we have previously demonstrated abnormal methylation of DNA associated with thebrain-derived neurotrophic factor(Bdnf) gene in the medial prefrontal cortex (mPFC) of adult rats. The aim of the current study was to characterizeBdnfDNA methylation in specific cell populations within the mPFC. In the prefrontal cortex, there is approximately twice as many neurons as glia, and studies have recently shown differential and distinctive DNA methylation patterns in neurons versus nonneurons. Here, we extracted nuclei from the mPFC of adult animals that had experienced maltreatment and used fluorescence-activated cell sorting to isolate cell types before performing bisulfite sequencing to estimate methylation of cytosine–guanine sites. Our data indicate that early-life stress induced methylation of DNA associated withBdnf IVin a cell-type and sex-specific manner. Specifically, females that experienced early-life maltreatment exhibited greater neuronal cytosine–guanine methylation compared to controls, while no changes were detected inBdnfmethylation in males regardless of cell type. These changes localize the specificity of our previous findings to mPFC neurons and highlight the capacity of maltreatment to cause methylation changes that are likely to have functional consequences for neuronal function.

scholarly journals Epigenetic reprogramming of cell identity: lessons from development for regenerative medicine

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Amitava Basu ◽  
Vijay K. Tiwari
Keyword(s):  
Regenerative Medicine ◽  
Cell Types ◽  
Direct Conversion ◽  
Cellular Reprogramming ◽  
Specific Cell ◽  
Cell Type ◽  
Pathological Conditions ◽  
Gene Regulatory ◽  
Induced Pluripotent ◽  
And Function

AbstractEpigenetic mechanisms are known to define cell-type identity and function. Hence, reprogramming of one cell type into another essentially requires a rewiring of the underlying epigenome. Cellular reprogramming can convert somatic cells to induced pluripotent stem cells (iPSCs) that can be directed to differentiate to specific cell types. Trans-differentiation or direct reprogramming, on the other hand, involves the direct conversion of one cell type into another. In this review, we highlight how gene regulatory mechanisms identified to be critical for developmental processes were successfully used for cellular reprogramming of various cell types. We also discuss how the therapeutic use of the reprogrammed cells is beginning to revolutionize the field of regenerative medicine particularly in the repair and regeneration of damaged tissue and organs arising from pathological conditions or accidents. Lastly, we highlight some key challenges hindering the application of cellular reprogramming for therapeutic purposes.

scholarly journals Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens

2021 ◽  
Author(s):  
Hee-Dae Kim ◽  
Jing Wei ◽  
Tanessa Call ◽  
Nicole Teru Quintus ◽  
Alexander J. Summers ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Current Treatment ◽  
Specific Cell ◽  
Excitatory Synapses ◽  
Cell Type ◽  
Cell Type Specific ◽  
Specific Regulation ◽  
Circuit Function

AbstractDepression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

scholarly journals EMeth: An EM algorithm for cell type decomposition based on DNA methylation data

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hanyu Zhang ◽  
Ruoyi Cai ◽  
James Dai ◽  
Wei Sun
Keyword(s):  
Dna Methylation ◽  
Tumor Cells ◽  
T Regulatory Cells ◽  
Simulated Data ◽  
Cell Types ◽  
Computational Method ◽  
Methylation Data ◽  
Cell Type ◽  
A Cell ◽  
Type Decomposition

AbstractWe introduce a new computational method named EMeth to estimate cell type proportions using DNA methylation data. EMeth is a reference-based method that requires cell type-specific DNA methylation data from relevant cell types. EMeth improves on the existing reference-based methods by detecting the CpGs whose DNA methylation are inconsistent with the deconvolution model and reducing their contributions to cell type decomposition. Another novel feature of EMeth is that it allows a cell type with known proportions but unknown reference and estimates its methylation. This is motivated by the case of studying methylation in tumor cells while bulk tumor samples include tumor cells as well as other cell types such as infiltrating immune cells, and tumor cell proportion can be estimated by copy number data. We demonstrate that EMeth delivers more accurate estimates of cell type proportions than several other methods using simulated data and in silico mixtures. Applications in cancer studies show that the proportions of T regulatory cells estimated by DNA methylation have expected associations with mutation load and survival time, while the estimates from gene expression miss such associations.

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