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 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 HDAC1 links early life stress to schizophrenia-like phenotypes

2017 ◽  
Vol 114 (23) ◽  
pp. E4686-E4694 ◽  
Author(s):  
Sanaz Bahari-Javan ◽  
Hristo Varbanov ◽  
Rashi Halder ◽  
Eva Benito ◽  
Lalit Kaurani ◽  
...  
Keyword(s):  
Risk Factors ◽  
Dna Methylation ◽  
Prefrontal Cortex ◽  
Histone Deacetylase ◽  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Blood Samples ◽  
Histone Deacetylase 1 ◽  
Disease Phenotypes

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

scholarly journals Investigating peripubertal stress and exogenous corticosterone as endogenous stimulators of brain metabolism

2020 ◽  
Author(s):  
Nathalie Just
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Acute Stress ◽  
Lactate Concentration ◽  
Early Life Stress ◽  
Resonance Spectroscopy ◽  
Adult Rats ◽  
Concentration Changes ◽  
As Stress ◽  
And Behavior

AbstractSubstantial research on the association between early-life stress and its long-lasting impact on lifetime mental health has been performed revealing that early-life environmental adversity strongly regulates brain function. Alterations of gene expression and behavior in the off-springs of paternally stressed rats were also revealed. However, the precise mechanisms underlying these changes remain poorly understood. Here, an improved characterization of these processes from investigations of the functional metabolism of animal models exposed to peripubertal stress (PS) is proposed. The ultimate goal of this study was to bring forward functional Magnetic Resonance Spectroscopy (fMRS) as a technique of interest for a better understanding of brain areas by endogenous stimulators such as stress. The present study evaluated, compared and classified effects of individual PS (iPS) and paternal PS (pPS) under corticosterone (CORT) challenge in the septal areas of adult rats. Acute stress was simulated by injection of CORT and metabolic concentration changes were analyzed as a function of time. Evaluation of Glucose and Lactate concentration changes allowed the classification of groups of rats using a Glc to Lac index. Moreover, metabolic responses of control rats (CC) and of pPS x iPS rats (SS) were similar while responses in pPS (SC) and iPS (CS) differed, revealing differential adaption of energetic metabolism and of glutamatergic neurotransmission. Findings have crucial interest for understanding the metabolic mechanisms underlying altered functional connectivity and neuronal plasticity in septal areas inducing increased aggressivity in early-life stressed rats.

The effects of early life stress on context fear generalization in adult rats.

2019 ◽  
Vol 133 (1) ◽  
pp. 50-58 ◽  
Author(s):  
Nathalie D. Elliott ◽  
Rick Richardson
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Early Life Stress ◽  
Adult Rats ◽  
Fear Generalization

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.

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