Epigenetics in the nervous system

  • Article
    | Open Access

    α-ketoglutarate (αKG) is an intermediate in the tricarboxylic acid cycle that is required in the nucleus for genomic DNA demethylation by Tet3. Here, the authors show that the enzyme glutamate dehydrogenase, which converts glutamate to αKG, is redirected from the mitochondria to the nucleus.

    • Franziska R. Traube
    • , Dilara Özdemir
    •  & Thomas Carell
  • Article
    | Open Access

    The cellular heterogeneity in brain obscures the identification of robust cellular regulatory networks. Here the authors integrate genome-wide chromosome conformation data from sorted neurons and glia, with transcriptomic and enhancer profiles, to characterize cell-type-specific gene regulatory landscapes in the human brain, and provide insights into cell-type-specific gene regulatory networks in brain disorders.

    • Benxia Hu
    • , Hyejung Won
    •  & Daniel H. Geschwind
  • Article
    | Open Access

    Although epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, previous studies have been limited in sample size and brain region used. Here, the authors combine data from six DNA methylomic studies of Alzheimer’s disease (N = 1453 unique individuals) to identify differentially methylated loci across cortex.

    • Rebecca G. Smith
    • , Ehsan Pishva
    •  & Katie Lunnon
  • Article
    | Open Access

    DNA methylation plays an important role in brain development and function. Here, the authors compare whole-genome methylation in neurons and oligodendrocytes in humans, chimpanzees and macaques to reconstruct evolution of DNA methylation at cell-type level, including in regions associated with schizophrenia heritability.

    • Hyeonsoo Jeong
    • , Isabel Mendizabal
    •  & Soojin V. Yi
  • Article
    | Open Access

    Here, the authors perform ATAC-seq on four distinct cell populations from three different regions of the human brain, finding that chromatin accessibility varies greatly by cell type and less by brain region. This study reveals differences in biological function and gene regulation, as well as overlap of genetic variants associated with schizophrenia and other neuropsychiatric traits.

    • Mads E. Hauberg
    • , Jordi Creus-Muncunill
    •  & Panos Roussos
  • Article
    | Open Access

    Epigenetic mechanisms have emerged as contributors to the molecular impairments caused by exposure to environmental factors such as abused substances. Here the authors perform epigenetic profiling of the striatum and identify the tyrosine kinase FYN is an important driver of neurodegenerative-like pathology and drug-taking behaviour.

    • Gabor Egervari
    • , Diana Akpoyibo
    •  & Yasmin L. Hurd
  • Article
    | Open Access

    Myelination by Schwann cells (SC) in the peripheral nervous system is essential for motor function, and dysregulation of SC myelination can lead to various neuropathies. Here the authors describe a critical role of CCCTC-binding factor (CTCF)-dependent chromatin reorganization in peripheral myelination and myelin regeneration after injury.

    • Jincheng Wang
    • , Jiajia Wang
    •  & Q. Richard Lu
  • Article
    | Open Access

    Polycomb repressive complex 2 (PRC2) methylates H3K27 and suppresses RNA polymerase II transcription by promoting a closed chromatin. Here the authors identify the transcription factor Ybx1 as an interactor that regulates the binding of PRC2 to chromatin and H3K27 methylation to promote the genetic programs underlying neural lineages and neural progenitor self-renewal–differentiation choices.

    • Myron K. Evans
    • , Yurika Matsui
    •  & Jamy C. Peng
  • Article
    | Open Access

    Memories are encoded within neuronal ensembles activated during learning. Here the authors show that DNA methylation within neuronal ensembles contributes to the stability of the memory trace, and increases the likelihood of neuronal ensemble reactivation during retrieval.

    • Kubra Gulmez Karaca
    • , Janina Kupke
    •  & Ana M. M. Oliveira
  • Article
    | Open Access

    AgRP neurons in the hypothalamic arcuate nucleus (ARH) are involved in regulating hunger and energy balance. Here the authors show that knockout of the DNA methyltransferase Dnmt3a in AgRP neurons of the ARH leads to a reduction in voluntary exercise along with numerous epigenetic and gene expression changes in ARH neurons.

    • Harry MacKay
    • , C. Anthony Scott
    •  & Robert A. Waterland
  • Article
    | Open Access

    It’s well known that hippocampal synaptic plasticity and memory are impaired in experimental models of metabolic diseases, however, it is unclear if maternal diet or metabolic alterations around the gestational age may multigenerationally affect learning and memory. In this study, authors demonstrate that maternal high fat diet-dependent insulin resistance affects synaptic plasticity and memory of descendants until the third generation via reduced exon specific brain-derived neurotrophic factor expression in the hippocampus of descendants

    • Salvatore Fusco
    • , Matteo Spinelli
    •  & Claudio Grassi
  • Article
    | Open Access

    The molecular mechanisms of memory storage remain poorly understood. In this study, authors describe a new mechanism that regulates the cellular patterns of early response gene signaling during learning via the recruitment of two functionally redundant nuclear repressors, class IIa histone deacetylases (HDACs) 4 and 5

    • Yongchuan Zhu
    • , Min Huang
    •  & Anton Maximov
  • Article
    | Open Access

    DNA methylation plays an important role in silencing transposable elements. Here the authors find that loss of DNMT1 and DNA methylation leads to transcriptional activation and chromatin remodelling of evolutionarily young—hominoid-specific —LINE-1 elements which then act as alternative promoters for neuronal genes.

    • Marie E Jönsson
    • , Per Ludvik Brattås
    •  & Johan Jakobsson
  • Article
    | Open Access

    Gene transcription is known to vary with age and sex, although the underlying mechanisms are unresolved. Here, the authors show that epigenetic enzymes known as HDACs, which regulate gene transcription, are increasingly expressed with age in the living human brain, with sex differences also observed.

    • Tonya M. Gilbert
    • , Nicole R. Zürcher
    •  & Jacob M. Hooker
  • Article
    | Open Access

    The molecular mechanisms underlying the dynamic nature of the female brain structure and function remain poorly understood. Here the authors characterise chromatin organization in the mouse female ventral hippocampus, finding it fluctuates with the oestrous cycle, and identify changes in chromatin organization associated with the transcription of genes important for neuronal function and behaviour.

    • Ivana Jaric
    • , Devin Rocks
    •  & Marija Kundakovic
  • Article
    | Open Access

    Despite the known role of midbrain dopaminergic (mDA) signaling in the homeostatic control of mood and motor functions, little is known about how gene expression in these neurons is regulated. Here, authors develop an in vivo nuclear tagging and capture technique for low-input chromatin accessibility and transcriptome profiling of genetically-defined neuron populations to identify Gmeb1 as a novel transcriptional regulator of mDA neurons, whose loss of function impairs motor control in mice.

    • Luis M. Tuesta
    • , Mohamed N. Djekidel
    •  & Yi Zhang
  • Article
    | Open Access

    Circadian rhythms are known to modulate memory, but it’s not known whether clock genes in the hippocampus are required for memory consolidation. Here, the authors show that epigenetic regulation of clock gene Period1 in the hippocampus regulates memory and contributes to age-related memory decline, independent of circadian rhythms.

    • Janine L. Kwapis
    • , Yasaman Alaghband
    •  & Marcelo A. Wood
  • Article
    | Open Access

    Myelin-forming cells derive from oligodendrocyte progenitors. Here the authors identify histone arginine methyl-transferase PRMT5 as critical for developmental myelination by modulating the cross-talk between histone arginine methylation and lysine acetylation, to favor differentiation.

    • Antonella Scaglione
    • , Julia Patzig
    •  & Patrizia Casaccia
  • Article
    | Open Access

    Anorexia nervosa is characterised by self-starvation but its etiology is not completely understood. Here the authors describe how prenatal stress can induce activity-based anorexia in the offspring during early adulthood by upregulating miR-340 expression in the placenta that affects expression of nutrient transporters.

    • Mariana Schroeder
    • , Mira Jakovcevski
    •  & Alon Chen
  • Article
    | Open Access

    The limited size of some neuronal types and their entangled environment renders it difficult to study their transcription regulation. Here the authors present a comparative analysis of histone modifications and transcription in dopaminergic and serotonergic neurons and embryonic neural progenitors.

    • Erik Södersten
    • , Konstantinos Toskas
    •  & Johan Holmberg
  • Article
    | Open Access

    Before the onset of puberty, Polycomb proteins repress the expression of Kiss1 in KNDy neurons of the arcuate nucleus. Here, by CRISPR-Cas9-directed epigenome editing and RNAi, the authors show that coordinated action of Mll proteins at the Kiss1 promoter and enhancer is required for correct timing of puberty.

    • Carlos A. Toro
    • , Hollis Wright
    •  & Alejandro Lomniczi
  • Article
    | Open Access

    Most SNPs are located in non-coding genomic regions and their function remains elusive. Here, the authors perform a genome-wide scan of expression and DNA methylation quantitative trait loci in human hippocampal tissue to provide a resource for the functional interpretation of SNPs in brain disorders.

    • Herbert Schulz
    • , Ann-Kathrin Ruppert
    •  & Sven Cichon
  • Article
    | Open Access

    “LSD1 is a histone demethylase that plays many roles during development. Here, the authors provide evidence that loss of LSD1 in adult mice leads to paralysis and neurodegeneration in the hippocampus and cortex and suggest a potential link between LSD1 and human neurodegenerative disease.

    • Michael A. Christopher
    • , Dexter A. Myrick
    •  & David J. Katz
  • Article
    | Open Access

    miR-132/212 has been implicated in ocular dominance plasticity during the critical period. Here the authors show that miR-132/212 regulates the expression of genes involved in visual cortex maturation, and that mice lack miR-132/212 show deficits in binocular matching of orientation preferences, which leads to impaired depth perception.

    • Raffaele Mazziotti
    • , Laura Baroncelli
    •  & Tommaso Pizzorusso
  • Article
    | Open Access

    Transcriptional regulation is necessary for maintaining long-term memories (LTM) but the mechanistic details are not completely defined. Here the authors identify transcriptional machinery and histone modifiers required for LTM maintenance inDrosophilaand show that transcriptional regulation for LTM maintenance is distinct from that for LTM formation.

    • Yukinori Hirano
    • , Kunio Ihara
    •  & Minoru Saitoe
  • Article
    | Open Access

    Chromosome conformation is a dynamic process, especially in brain. Here, Mitchell and colleagues devise a method they call NeuroDam that can prospectively tag chromosome conformation in the mouse brain in vivo, and longitudinally assess long range chromosome looping weeks and months later.

    • Amanda C. Mitchell
    • , Behnam Javidfar
    •  & Schahram Akbarian
  • Article
    | Open Access

    Protein phosphatase1 (PP1), a signalling and transcriptional regulator, and epigenetic modulator is known to be a memory suppressor. Here the authors show that memory control by PP1 involves the microRNA cluster miR-183/96/182, and that this cluster is selectively regulated during memory formation in mice.

    • Bisrat T. Woldemichael
    • , Ali Jawaid
    •  & Isabelle M. Mansuy
  • Article
    | Open Access

    Physiological effects of psychological stress and infection in mothers can increase the incidence of anxiety and psychiatric diseases in offsprings and in subsequent generation. Here, Miklos Toth and colleagues show that intergenerational inheritance of neurological traits is propagated across multiple generations independently by parallel non-genetic mechanisms involving independent segregation of epigenetic specific loci.

    • Emma Mitchell
    • , Shifra L. Klein
    •  & Miklos Toth
  • Article
    | Open Access

    The great tit (Parus major) is known for its complex social-cognitive behaviour. Here, the authors sequence genomes of the great tit and show genes related to learning and cognition in regions under positive selection, as well as neuronal non-CpG methylation patterns similar to those observed in mammals.

    • Veronika N. Laine
    • , Toni I. Gossmann
    •  & Martien A. M. Groenen
  • Article
    | Open Access

    Epigenetic regulation plays a key role in cortical development. Here the authors show that Rcor2, a co-repressor of the histone demethylase LSD1/KDM1A complex, regulates neural progenitor cell proliferation and cortical neurogenesis by repressing sonic hedgehog signaling.

    • Yixuan Wang
    • , Qian Wu
    •  & Xiaoqun Wang
  • Article
    | Open Access

    Neurons in the brain are more susceptible to oxidative stress than astroglial cells but the molecular basis and biological reasons for this are poorly understood. Here the authors show that developing cortical neurons have reduced levels of the antioxidant transcription factor Nrf2 due to epigenetic silencing and that this is necessary for proper neuronal development.

    • Karen F.S. Bell
    • , Bashayer Al-Mubarak
    •  & Giles E. Hardingham
  • Article |

    Traumatic events in one generation can affect the behaviour of their offspring. Here the authors subject male mouse pups to traumatic stress and find that their offspring display improved goal-directed behaviours associated with epigenetic changes of the mineralocorticoid receptor gene.

    • Katharina Gapp
    • , Saray Soldado-Magraner
    •  & Isabelle M. Mansuy
  • Article |

    It is becoming increasingly clear that the three-dimensional organization of chromatin within the nucleus plays a role in regulating gene expression. Here, Ito et al.demonstrate that the disruption of chromocenter clustering in mature neuronal cells results in specific transcriptional and behavioural defects in mice.

    • Satomi Ito
    • , Adriana Magalska
    •  & Angel Barco