Cerebellum

Publication Title: 
Archives of General Psychiatry

CONTEXT: Although most of the effort to understand the neurobiology of depressive states and suicide has focused on neuronal processes, recent studies suggest that astroglial dysfunction may play an important role. A truncated variant of the tropomyosin-related kinase B (TrkB.T1) is expressed in astrocytes, and brain-derived neurotrophic factor-TrkB signaling has been linked to mood disorders. OBJECTIVE: To test the hypothesis that TrkB.T1 expression is downregulated in suicide completers and that this downregulation is mediated by an epigenetic process.

Author(s): 
Ernst, Carl
Deleva, Vesselina
Deng, Xiaoming
Sequeira, Adolfo
Pomarenski, Amanda
Klempan, Tim
Ernst, Neil
Quirion, Rémi
Gratton, Alain
Szyf, Moshe
Turecki, Gustavo
Publication Title: 
Epigenetics

IGF2 is a paternally expressed imprinted gene with an important role in development and brain function. Allele-specific expression of IGF2 is regulated by DNA methylation at three differentially methylated regions (DMRs) spanning the IGF2/H19 domain on human 11p15.5. We have comprehensively assessed DNA methylation and genotype across the three DMRs and the H19 promoter using tissue from a unique collection of well-characterized and neuropathologically-dissected post-mortem human cerebellum samples (n = 106) and frontal cortex samples (n = 51).

Author(s): 
Pidsley, Ruth
Dempster, Emma
Troakes, Claire
Al-Sarraj, Safa
Mill, Jonathan
Publication Title: 
Molecular Psychiatry

Adenosine-to-inosine (A-to-I) RNA editing is a neurodevelopmentally regulated epigenetic modification shown to modulate complex behavior in animals. Little is known about human A-to-I editing, but it is thought to constitute one of many molecular mechanisms connecting environmental stimuli and behavioral outputs. Thus, comprehensive exploration of A-to-I RNA editing in human brains may shed light on gene-environment interactions underlying complex behavior in health and disease.

Author(s): 
Eran, A.
Li, J. B.
Vatalaro, K.
McCarthy, J.
Rahimov, F.
Collins, C.
Markianos, K.
Margulies, D. M.
Brown, E. N.
Calvo, S. E.
Kohane, I. S.
Kunkel, L. M.
Publication Title: 
Molecular Brain

BACKGROUND: Insulin-like growth factor 2 (Igf2) is a paternally expressed imprinted gene regulating fetal growth, playing an integral role in the development of many tissues including the brain. The parent-of-origin specific expression of Igf2 is largely controlled by allele-specific DNA methylation at CTCF-binding sites in the imprinting control region (ICR), located immediately upstream of the neighboring H19 gene. Previously we reported evidence of a negative correlation between DNA methylation in this region and cerebellum weight in humans.

Author(s): 
Pidsley, Ruth
Fernandes, Cathy
Viana, Joana
Paya-Cano, Jose L.
Liu, Lin
Smith, Rebecca G.
Schalkwyk, Leonard C.
Mill, Jonathan
Publication Title: 
Translational Psychiatry

The elucidation of epigenetic alterations in the autism brain has potential to provide new insights into the molecular mechanisms underlying abnormal gene expression in this disorder. Given strong evidence that engrailed-2 (EN-2) is a developmentally expressed gene relevant to cerebellar abnormalities and autism, the epigenetic evaluation of this candidate gene was undertaken in 26 case and control post-mortem cerebellar samples. Assessments included global DNA methylation, EN-2 promoter methylation, EN-2 gene expression and EN-2 protein levels.

Author(s): 
James, S. J.
Shpyleva, Svitlana
Melnyk, Stepan
Pavliv, Oleksandra
Pogribny, I. P.
Publication Title: 
Molecular Psychiatry

Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders defined clinically by a triad of features including impairment in social interaction, impairment in communication in social situations and restricted and repetitive patterns of behavior and interests, with considerable phenotypic heterogeneity among individuals. Although heritability estimates for ASD are high, conventional genetic-based efforts to identify genes involved in ASD have yielded only few reproducible candidate genes that account for only a small proportion of ASDs.

Author(s): 
Ladd-Acosta, C.
Hansen, K. D.
Briem, E.
Fallin, M. D.
Kaufmann, W. E.
Feinberg, A. P.
Publication Title: 
Epigenetics

Klinefelter syndrome (KS) is the most common sex-chromosome aneuploidy in humans. Most affected individuals carry one extra X-chromosome (47,XXY karyotype) and the condition presents with a heterogeneous mix of reproductive, physical and psychiatric phenotypes. Although the mechanism(s) by which the supernumerary X-chromosome determines these features of KS are poorly understood, skewed X-chromosome inactivation (XCI), gene-dosage dysregulation, and the parental origin of the extra X-chromosome have all been implicated, suggesting an important role for epigenetic processes.

Author(s): 
Viana, Joana
Pidsley, Ruth
Troakes, Claire
Spiers, Helen
Wong, Chloe Cy
Al-Sarraj, Safa
Craig, Ian
Schalkwyk, Leonard
Mill, Jonathan
Publication Title: 
Biological Psychiatry

BACKGROUND: Adolescent depression is a common neuropsychiatric disorder that often continues into adulthood and is associated with a wide range of poor outcomes including suicide. Although numerous studies have looked at genetic markers associated with depression, the role of epigenetic variation remains relatively unexplored. METHODS: Monozygotic (MZ) twins were selected from an adolescent twin study designed to investigate the interplay of genetic and environmental factors in the development of emotional and behavioral difficulties.

Author(s): 
Dempster, Emma L.
Wong, Chloe C. Y.
Lester, Kathryn J.
Burrage, Joe
Gregory, Alice M.
Mill, Jonathan
Eley, Thalia C.
Publication Title: 
Translational Psychiatry

Epigenetic mechanisms regulate programmed gene expression during prenatal neurogenesis and serve as a mediator between genetics and environment in postnatal life. The recent discovery of 5-hydroxymethylcytosine (5-hmC), with highest concentration in the brain, has added a new dimension to epigenetic regulation of neurogenesis and the development of complex behavior disorders. Here, we take a candidate gene approach to define the role 5-hmC in Engrailed-2 (EN-2) gene expression in the autism cerebellum.

Author(s): 
James, S. J.
Shpyleva, S.
Melnyk, S.
Pavliv, O.
Pogribny, I. P.
Publication Title: 
Genome Biology

BACKGROUND: Schizophrenia is a severe neuropsychiatric disorder that is hypothesized to result from disturbances ine arly brain development. There is mounting evidence to support a role for developmentally regulated epigenetic variation in the molecular etiology of the disorder. Here, we describe a systematic study of schizophrenia-associated methylomic variation in the adult brain and its relationship to changes in DNA methylation across human fetal brain development.

Author(s): 
Pidsley, Ruth
Viana, Joana
Hannon, Eilis
Spiers, Helen
Troakes, Claire
Al-Saraj, Safa
Mechawar, Naguib
Turecki, Gustavo
Schalkwyk, Leonard C.
Bray, Nicholas J.
Mill, Jonathan

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