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| Open AccessMaternal dietary fat during lactation shapes single nucleus transcriptomic profile of postnatal offspring hypothalamus in a sexually dimorphic manner in mice
Maternal high fat diet during lactation predisposes offspring to develop obesity in males more than females. Here, authors show expansion of key metabolic related hypothalamic neuron populations in male but not female mice, in response to maternal fat intake.
- Yi Huang
- , Anyongqi Wang
- & John R. Speakman
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Article
| Open AccessKdm1a safeguards the topological boundaries of PRC2-repressed genes and prevents aging-related euchromatinization in neurons
Kdm1a is a histone demethylase implicated in intellectual disability. Here, the authors show that removing Kdm1a in neurons of the adult mouse forebrain disrupts silencing of nonneuronal genes and chromatin organization, emphasizing its role in preserving neuronal genome integrity.
- Beatriz del Blanco
- , Sergio Niñerola
- & Ángel Barco
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| Open AccessChronic oxytocin administration stimulates the oxytocinergic system in children with autism
Intranasal administration of oxytocin is increasingly considered as a new therapeutic option for alleviating stress and social problems in children with autism. Here, important insights are provided into how repeated administration of oxytocin influences the functioning of one’s own oxytocin system.
- Matthijs Moerkerke
- , Nicky Daniels
- & Kaat Alaerts
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Article
| Open AccessUSP7/Maged1-mediated H2A monoubiquitination in the paraventricular thalamus: an epigenetic mechanism involved in cocaine use disorder
This study uncovers the role of epigenetic H2A monoubiquitination in the mouse brain’s response to chronic cocaine use. It also identifies genetic variations in humans linked to H2A monoubiquitination, modifying susceptibility to cocaine addiction and aggression, and paving the way for tailored treatments.
- Julian Cheron
- , Leonardo Beccari
- & Alban de Kerchove d’Exaerde
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| Open AccessBrain methylome remodeling selectively regulates neuronal activity genes linking to emotional behaviors in mice exposed to maternal immune activation
How early life experience impacts adult behavior is unclear. Here, authors show that maternal immune activation remodels mouse brain methylome and selectively regulates neuronal activity genes, resulting in anxiety- and depression-like behaviors.
- Li Ma
- , Feng Wang
- & Jian-Fu Chen
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Article
| Open AccessEpigenetic regulation of beta-endorphin synthesis in hypothalamic arcuate nucleus neurons modulates neuropathic pain in a rodent pain model
Neuropathic pain is a complex and often disabling condition with unclear pathogenesis. Here, the authors elucidate an epigenetic regulatory pathway driven by microRNA regulation of betaendorphin (β-EP) synthesis in the hypothalamic arcuate nucleus (ARC) neurons to modulate neuropathic pain.
- Yu Tao
- , Yuan Zhang
- & Jin Tao
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Article
| Open AccessDivergent single cell transcriptome and epigenome alterations in ALS and FTD patients with C9orf72 mutation
Non-coding repeat expansion in the C9ORF72 gene is the most frequent cause of ALS and frontotemporal dementia. Here, the authors performed single cell analyses of gene expression and epigenetic regulation in these patients’ brains and emphasized the role of astrocytes and neurons in neurodegeneration.
- Junhao Li
- , Manoj K. Jaiswal
- & Stella Dracheva
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| Open AccessInheritance of associative memories and acquired cellular changes in C. elegans
Here the authors demonstrate that in C. elegans, aversive associative memory and associated cellular changes, are passed on to F1 and F2 progeny.
- Noa Deshe
- , Yifat Eliezer
- & Alon Zaslaver
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Article
| Open AccessInhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model
The study by Williams et al shows targeting the aberrant histone modifying enzyme Smyd3 rescues NMDAR and cognitive deficits in a mouse model of Alzheimer’s disease. It highlights the potential of epigenetic treatment in neurodegenerative diseases.
- Jamal B. Williams
- , Qing Cao
- & Zhen Yan
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Article
| Open AccessCell-type specific profiling of histone post-translational modifications in the adult mouse striatum
Bulk or pooled epigenomic profiling in the heterogenous brain obscures cell-type-specificity and individual subject variability in gene regulation. Here the authors optimized a hybrid protocol, ICuRuS, to profile epigenetic features in neuronal subtypes from a single mouse.
- Marco D. Carpenter
- , Delaney K. Fischer
- & Elizabeth A. Heller
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Article
| Open AccessHigh-throughput robust single-cell DNA methylation profiling with sciMETv2
Despite the importance of DNA methylation, accessible and high-throughput methods to profile methylation at the single-cell level are lacking. Here, the authors present sciMETv2, a high-throughput workflow that provides high-quality single-cell methylomes in a robust and simple workflow.
- Ruth V. Nichols
- , Brendan L. O’Connell
- & Andrew C. Adey
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Article
| Open AccessRescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome
The molecular mechanisms underlying deficits in Down syndrome remain unclear. Here, the authors show that copy number restoration of a chromatin remodeler in trisomic mice is sufficient to rescue epigenomic, physiological and cognitive deficits.
- Sasha L. Fulton
- , Wendy Wenderski
- & Ian Maze
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| Open AccessAn epigenome atlas of neural progenitors within the embryonic mouse forebrain
The authors took a multimodal approach to characterize the differential transcriptome and epigenetic landscape between distinct regions of the embryonic mouse forebrain, revealing many unexplored presumptive promoter-enhancer interactions.
- Christopher T. Rhodes
- , Joyce J. Thompson
- & Timothy J. Petros
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| Open AccessComparison of chromatin accessibility landscapes during early development of prefrontal cortex between rhesus macaque and human
The evolution of epigenetic regulation of brain development in primates is not well understood. Here, the authors perform a comparative study of epigenetic dynamics of early prefrontal cortex development between human and rhesus macaque, finding divergent regulatory elements that may be related to cognitive capacity.
- Xuelong Yao
- , Zongyang Lu
- & Jiang Liu
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| Open AccessSex-specific multi-level 3D genome dynamics in the mouse brain
Here the authors provide evidence that 3D chromatin structure in the mouse brain differs between males and females and undergoes dynamic remodelling during the female ovarian cycle. They show female-specific 3D genome dynamics affects neuronal gene expression and brain disorder-relevant genes, and could play a role in reproductive hormone-induced brain plasticity and female-specific risk for brain disorders.
- Devin Rocks
- , Mamta Shukla
- & Marija Kundakovic
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Article
| Open AccessCellular and genetic drivers of RNA editing variation in the human brain
Here the authors provide a deep catalogue of cell-specific A-to-I editing sites in the human cortex. Thousands of sites are enriched and elevated in neurons relative to glial cells, and are genetically regulated across multiple brain regions.
- Winston H. Cuddleston
- , Junhao Li
- & Michael S. Breen
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Article
| Open AccessAstroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes
Astroblastoma (AB) is an uncommon brain tumour and its origin remains unknown. Here, the authors perform integrative molecular analysis of 35 AB-like tumours and provide evidence that these arise in the context of epigenetic and genetic changes in neural progenitors occurring during brain development.
- Norman L. Lehman
- , Nathalie Spassky
- & Akshitkumar M. Mistry
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| Open AccessThe Oligodendrocyte Transcription Factor 2 OLIG2 regulates transcriptional repression during myelinogenesis in rodents
Transcription factors regulate gene programs during myelination. Here, the authors show that the Oligodendrocyte Transcription Factor 2 (OLIG2) regulates the differentiation of oligodendrocyte progenitor cells into immature oligodendrocytes via SETDB1 during myelination and remyelination in rodents.
- Kunkun Zhang
- , Shaoxuan Chen
- & Wei Mo
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Article
| Open AccessOrganic anion transporter 1 is an HDAC4-regulated mediator of nociceptive hypersensitivity in mice
Chronic pain is sustained by alterations in gene transcription. Here, the authors show that increased expression of Organic Anionic Transporter 1 in the spinal cord is epigenetically controlled and key to hypersensitivity in pathological pain.
- Christian Litke
- , Anna M. Hagenston
- & Daniela Mauceri
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| Open AccessIdentification of a modular super-enhancer in murine retinal development
Super-enhancers are regions of genomic DNA comprised of multiple putative enhancers that contribute to dynamic gene expression patterns during development. Here the authors identify a modular super-enhancer in murine retinal development and show that distinct modules are responsible for retinal progenitor cell proliferation during early and bipolar neuron genesis during late retinal development.
- Victoria Honnell
- , Jackie L. Norrie
- & Michael A. Dyer
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| Open AccessNeuronal Yin Yang1 in the prefrontal cortex regulates transcriptional and behavioral responses to chronic stress in mice
The mechanisms underlying the chronic stress-induced increased risk for major depressive disorder and anxiety are unclear. Here, the authors show the transcriptional changes occurring in neocortical neurons and identify YY1 as a regulator of chronic stress-induced maladaptive behavior in mice.
- Deborah Y. Kwon
- , Bing Xu
- & Zhaolan Zhou
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Article
| Open AccessCHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum
CHARGE syndrome that affects cerebellar development can be caused by haploinsufficiency of the chromatin remodeling enzyme CHD7; however the precise role of CHD7 remains unknown. Here the authors show CHD7 promotes chromatin accessibility and enhancer activity in granule cell precursors and regulates morphogenesis of the cerebellar cortex, where loss of CHD7 triggers cerebellar polymicrogyria.
- Naveen C. Reddy
- , Shahriyar P. Majidi
- & Harrison W. Gabel
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Article
| Open AccessEpigenetic inactivation of the autophagy–lysosomal system in appendix in Parkinson’s disease
Dysfunction of the gastrointestinal system, and to the autophagy lysososmal pathway (ALP) have been reported in Parkinson’s disease. Here the authors report epigenetic disruption of ALP related genes in the appendix of individuals with Parkinson’s disease.
- Juozas Gordevicius
- , Peipei Li
- & Viviane Labrie
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Article
| Open AccessNeuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior
The link between tRNA modifications, protein translation, and behavior is unclear. Here, the authors show that neuronal Nsun2 deficiency results in codon-specific epitranscriptomic changes of Gly-tRNAs and proteomic changes affecting synaptic signaling and behavior in mice.
- J. Blaze
- , A. Navickas
- & S. Akbarian
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| Open AccessRedirected nuclear glutamate dehydrogenase supplies Tet3 with α-ketoglutarate in neurons
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
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| Open AccessNeuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders
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
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| Open AccessEnvironmental enrichment preserves a young DNA methylation landscape in the aged mouse hippocampus
Decline of brain function during aging is associated with epigenetic changes, including DNA methylation. Here the authors provide evidence that environmental enrichment delays age-related DNA methylation alterations in the mouse hippocampus.
- Sara Zocher
- , Rupert W. Overall
- & Gerd Kempermann
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| Open AccessCoordination of two enhancers drives expression of olfactory trace amine-associated receptors
In our nose, some neuron subpopulations express a family of trace amine associated receptors (TAARs, smelling e.g., rotten fish). Fei et al. identify two conserved enhancers across placental mammals named TAAR enhancer 1 and 2 that coordinately regulate expression of the entire Taar gene repertoire.
- Aimei Fei
- , Wanqing Wu
- & Qian Li
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Article
| Open AccessA meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex
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
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Article
| Open AccessEvolution of DNA methylation in the human brain
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
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Article
| Open AccessNon-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation
Early-life adversity is thought to increase the risk of psychopathology through epigenetic mechanisms. Here, the authors profile 6 histone marks, chromatin states and DNA methylation in the lateral amygdala in subjects with a history of early-life adversity.
- Pierre-Eric Lutz
- , Marc-Aurèle Chay
- & Gustavo Turecki
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| Open AccessCommon schizophrenia risk variants are enriched in open chromatin regions of human glutamatergic neurons
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
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Article
| Open AccessChromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder
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
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Article
| Open AccessCTCF-mediated chromatin looping in EGR2 regulation and SUZ12 recruitment critical for peripheral myelination and repair
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
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Article
| Open AccessYbx1 fine-tunes PRC2 activities to control embryonic brain development
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
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Article
| Open AccessCircGRIA1 shows an age-related increase in male macaque brain and regulates synaptic plasticity and synaptogenesis
Circular RNAs are expressed in the brain and show age-dependent expression patterns. Here the authors show the circGRIA1 is expressed in an age-dependent manner in the male macaque brain and serves a functional role in synaptic plasticity.
- Kaiyu Xu
- , Ying Zhang
- & Jiali Li
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Article
| Open AccessKAT3-dependent acetylation of cell type-specific genes maintains neuronal identity in the adult mouse brain
Neuronal identity maintenance is highly regulated. Here, the authors showed that CBP and p300 safeguard neuronal identity through histone acetylation at promoters and enhancers of neuronal specific genes. The loss of both CBP and p300 impairs gene expression, circuit activity, and behavior in mice.
- Michal Lipinski
- , Rafael Muñoz-Viana
- & Angel Barco
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Article
| Open AccessNeuronal ensemble-specific DNA methylation strengthens engram stability
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
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Article
| Open AccessDNA methylation in AgRP neurons regulates voluntary exercise behavior in mice
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
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Article
| Open AccessMaternal insulin resistance multigenerationally impairs synaptic plasticity and memory via gametic mechanisms
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
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Article
| Open AccessEGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity
It is unclear why neuronal activity induced methylation changes are limited to specific loci in the genome. Here, authors show that the DNA demethylation enzyme, TET1, gains its specificity via the interaction with EGR1, a sequence specific DNA binding protein.
- Zhixiong Sun
- , Xiguang Xu
- & Hehuang Xie
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Article
| Open AccessClass IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription
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
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Article
| Open AccessActivation of neuronal genes via LINE-1 elements upon global DNA demethylation in human neural progenitors
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
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Article
| Open AccessNeuroepigenetic signatures of age and sex in the living human brain
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
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Article
| Open AccessChromatin organization in the female mouse brain fluctuates across the oestrous cycle
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
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Article
| Open AccessIn vivo nuclear capture and molecular profiling identifies Gmeb1 as a transcriptional regulator essential for dopamine neuron function
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
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Article
| Open AccessEpigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory
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
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Article
| Open AccessEpigenome-wide DNA methylation profiling in Progressive Supranuclear Palsy reveals major changes at DLX1
Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by aggregation of Tau, encoded by MAPT. Here, the authors perform an EWAS for PSP in prefrontal lobe tissue and find hypermethylation of DLX1 and its antisense transcript DLX1AS to associate with MAPT expression.
- Axel Weber
- , Sigrid C. Schwarz
- & Ulrich Müller
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Article
| Open AccessPRMT5-mediated regulation of developmental myelination
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