The Future of Neuroepigenetics in the Human Brain

Mitchell, Amanda; Roussos, Panos; Peter, Cyril J.; Tsankova, Nadejda M.; Akbarian, Schahram

doi:10.1016/b978-0-12-800977-2.00008-5

Cited by 14 publications

(10 citation statements)

References 182 publications

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“…Additional treatment with nicotine in the same model significantly increased the number of astrocytes in the fetal hippocampus and resulted in reductions of both GFAP- and NeuN-positive cells in the CA1 in adulthood. It is important to note that comparing epigenetic landscapes of neuronal and glial cell genomes in normally and pathologically developing brains might in the future provide a powerful tool for creating genetic maps of normally developing and aging brain and provide clues for their changes in neurodegeneration (Mitchell et al, 2014 ).…”

Section: Epigenetic Consequences Of Prenatal Hypoxiamentioning

confidence: 99%

Role of Prenatal Hypoxia in Brain Development, Cognitive Functions, and Neurodegeneration

2018

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This review focuses on the role of prenatal hypoxia in the development of brain functions in the postnatal period and subsequent increased risk of neurodegenerative disorders in later life. Accumulating evidence suggests that prenatal hypoxia in critical periods of brain formation results in significant changes in development of cognitive functions at various stages of postnatal life which correlate with morphological changes in brain structures involved in learning and memory. Prenatal hypoxia also leads to a decrease in brain adaptive potential and plasticity due to the disturbance in the process of formation of new contacts between cells and propagation of neuronal stimuli, especially in the cortex and hippocampus. On the other hand, prenatal hypoxia has a significant impact on expression and processing of a variety of genes involved in normal brain function and their epigenetic regulation. This results in changes in the patterns of mRNA and protein expression and their post-translational modifications, including protein misfolding and clearance. Among proteins affected by prenatal hypoxia are a key enzyme of the cholinergic system-acetylcholinesterase, and the amyloid precursor protein (APP), both of which have important roles in brain function. Disruption of their expression and metabolism caused by prenatal hypoxia can also result, apart from early cognitive dysfunctions, in development of neurodegeneration in later life. Another group of enzymes affected by prenatal hypoxia are peptidases involved in catabolism of neuropeptides, including amyloid-β peptide (Aβ). The decrease in the activity of neprilysin and other amyloid-degrading enzymes observed after prenatal hypoxia could result over the years in an Aβ clearance deficit and accumulation of its toxic species which cause neuronal cell death and development of neurodegeneration. Applying various approaches to restore expression of neuronal genes disrupted by prenatal hypoxia during postnatal development opens an avenue for therapeutic compensation of cognitive dysfunctions and prevention of Aβ accumulation in the aging brain and the model of prenatal hypoxia in rodents can be used as a reliable tool for assessment of their efficacy.

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Section: Epigenetic Consequences Of Prenatal Hypoxiamentioning

confidence: 99%

Role of Prenatal Hypoxia in Brain Development, Cognitive Functions, and Neurodegeneration

2018

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“…Traditionally, ChIP-seq protocols have required relatively large amounts of sample (~10 million cells), limiting their application to the study of readily available tissue (Huang et al, 2006) (Furey, 2012). In addition, these approaches have traditionally employed tissue homogenates, thereby failing, by necessity, to address the cellular diversity found in the brain (Mitchell et al, 2014a). However, an increasing number of new methods have become available that are compatible with low-input (Adli and Bernstein, 2011; Brind’Amour et al, 2015; Jakobsen et al, 2015; Lara-Astiaso et al, 2014; Ng et al, 2013; Schmidl et al, 2015; Shankaranarayanan et al, 2011; Zwart et al, 2013).…”

Section: Chromatin Immunoprecipitation Followed By Sequencingmentioning

confidence: 99%

Understanding the genetic liability to schizophrenia through the neuroepigenome

Fullard

Halene

Giambartolomei

et al. 2016

Schizophrenia Research

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The Psychiatric Genomics Consortium-Schizophrenia Workgroup (PGC-SCZ) recently identified 108 loci associated with increased risk for schizophrenia (SCZ). The vast majority of these variants reside within non-coding sequences of the genome and are predicted to exert their effects by affecting the mechanism of action of cis regulatory elements (CREs), such as promoters and enhancers. Although a number of large-scale collaborative efforts (e.g. ENCODE) have achieved a comprehensive mapping of CREs in human cell lines or tissue homogenates, it is becoming increasingly evident that many risk-associated variants are enriched for expression Quantitative Trait Loci (eQTLs) and CREs in specific tissues or cells. As such, data derived from previous research endeavors may not capture fully cell-type and/or region specific changes associated with brain diseases. Coupling recent technological advances in genomics with cell-type specific methodologies, we are presented with an unprecedented opportunity to better understand the genetics of normal brain development and function and, in turn, the molecular basis of neuropsychiatric disorders. In this review, we will outline ongoing efforts towards this goal and will discuss approaches with the potential to shed light on the mechanism(s) of action of cell-type specific cis regulatory elements and their putative roles in disease, with particular emphasis on understanding the manner in which the epigenome and CREs influence the etiology of SCZ.

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“…It would thus be interesting to study this question systematically in the drug addiction field to obtain a complete overview of drug-induced regulation of the 3D structure of the entire genome. HiC techniques provide such a genome-wide interrogation and are now being applied increasingly to numerous systems including brain (36). It is not yet feasible to apply them to small brain regions but recent advances suggest that the technique should become suitable for smaller amounts of tissue (37).…”

Section: Discussionmentioning

confidence: 99%

Cocaine-Induced Chromatin Modifications Associate With Increased Expression and Three-Dimensional Looping of Auts2

Engmann

Labonté

Mitchell

et al. 2017

Biological Psychiatry

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Background Exposure to drugs of abuse alters the epigenetic landscape of the brain’s reward regions such as the nucleus accumbens (NAc). We investigated how combinations of chromatin modifications affect genes that regulate responses to cocaine. We focused on autism-candidate 2 (Auts2), a gene linked to human evolution and cognitive disorders, which displays strong clustering of cocaine-induced chromatin modifications in this brain region. Methods We combined chromosome conformation capture (4C and 3C) and related approaches with behavioral paradigms relevant to cocaine phenotypes. Cell type-specific functions were assessed by FACS-sorting and viral-mediated overexpression in Cre-dependent mouse lines. Results We observed that Auts2 gene expression is increased by repeated cocaine administration specifically in D2-type medium spiny neurons (MSNs) in NAc, an effect seen in male but not female mice. Auts2 mRNA expression was also upregulated postmortem in NAc of male human cocaine addicts. We obtained evidence that chromosomal looping, bypassing 1,524 kb of linear genome, connects Auts2 to the calneuron 1 (Caln1) gene locus under baseline conditions. This looping was disrupted after repeated cocaine exposure, resulting in increased expression of both genes in D2 MSNs. Cocaine exposure reduces binding of CTCF, a chromosomal scaffolding protein, and increases histone and DNA methylation, at the Auts-Caln1 loop base in NAc. Cell type-specific overexpression of Auts2 or Calnl in D2 MSNs demonstrated that both genes promote cocaine reward. Conclusions These findings suggest that cocaine-induced alterations of neuronal 3D genome organization destabilize higher order chromatin at specific loci that regulate responses to the drug.

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The Future of Neuroepigenetics in the Human Brain

Cited by 14 publications

References 182 publications

Role of Prenatal Hypoxia in Brain Development, Cognitive Functions, and Neurodegeneration

Role of Prenatal Hypoxia in Brain Development, Cognitive Functions, and Neurodegeneration

Understanding the genetic liability to schizophrenia through the neuroepigenome

Cocaine-Induced Chromatin Modifications Associate With Increased Expression and Three-Dimensional Looping of Auts2

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