The role of chromatin repressive marks in cognition and disease: A focus on the repressive complex GLP/G9a

Benevento, Marco; Molengraft, Marise van de; Westen, Rhode van; Bokhoven, Hans van; Kasri, Nael Nadif

doi:10.1016/j.nlm.2015.06.013

Cited by 49 publications

(41 citation statements)

References 113 publications

(149 reference statements)

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“…The core features of KS are intellectual disability (ID), hypotonia and cranio-facial abnormalities, frequently associated by various other conditions as congenital (heart) defects, epilepsy and Autism Spectrum Disorder (ASD)12. The effects of mutations in the Ehmt gene studied in Drosophila (EHMT) and in mouse models ( Ehmt1 ) at molecular, cellular and behavioural levels validated some core features of the Kleefstra syndrome34567891011.…”

mentioning

confidence: 89%

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Benevento

Oomen

Horner

et al. 2017

Sci Rep

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Heterozygous mutations or deletions of the human Euchromatin Histone Methyltransferase 1 (EHMT1) gene are the main causes of Kleefstra syndrome, a neurodevelopmental disorder that is characterized by impaired memory, autistic features and mostly severe intellectual disability. Previously, Ehmt1+/− heterozygous knockout mice were found to exhibit cranial abnormalities and decreased sociability, phenotypes similar to those observed in Kleefstra syndrome patients. In addition, Ehmt1+/− knockout mice were impaired at fear extinction and novel- and spatial object recognition. In this study, Ehmt1+/− and wild-type mice were tested on several cognitive tests in a touchscreen-equipped operant chamber to further investigate the nature of learning and memory changes. Performance of Ehmt1+/− mice in the Visual Discrimination & Reversal learning, object-location Paired-Associates learning- and Extinction learning tasks was found to be unimpaired. Remarkably, Ehmt1+/− mice showed enhanced performance on the Location Discrimination test of pattern separation. In line with improved Location Discrimination ability, an increase in BrdU-labelled cells in the subgranular zone of the dentate gyrus was observed. In conclusion, reduced levels of EHMT1 protein in Ehmt1+/− mice does not result in general learning deficits in a touchscreen-based battery, but leads to increased adult cell proliferation in the hippocampus and enhanced pattern separation ability.

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mentioning

confidence: 89%

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Benevento

Oomen

Horner

et al. 2017

Sci Rep

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“…The phosphorylation pattern of histone tails, which is tightly associated with histone acetylation, is regulated by nuclear kinases and protein phosphatases (Brami-Cherrier et al, 2009, Koshibu et al, 2009). In a similar fashion, histone methylation is catalyzed by histone methyltransferases (HMTs) such as G9a and SUV39H2, whereas demethylation of specific histone residues is dependent on histone demethylases (HDMs) such as lysine-specific demethylase 1A (LSD1) and jumonji domain-containing protein 2A (JMJD2) (Shin and Janknecht, 2007, Benevento et al, 2015). This array of histone modifications gives enormous potential for epigenetic responses, especially when considering that each of these changes can impact each other and may also interact with DNA methylation through recruitment of chromatin remodeling complexes.…”

Section: Epigenetics Mechanisms and Brainmentioning

confidence: 99%

Physical exercise as an epigenetic modulator of brain plasticity and cognition

Fernandes

Arida

Gómez‐Pinilla

2017

Neuroscience & Biobehavioral Reviews

224

172

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A large amount of evidence has demonstrated the power of exercise to support cognitive function, the effects of which can last for considerable time. An emerging line of scientific evidence indicates that the effects of exercise are longer lasting than previously thought up to the point to affect future generations. The action of exercise on epigenetic regulation of gene expression seem central to building an “epigenetic memory” to influence long-term brain function and behavior. In this review article, we discuss new developments in the epigenetic field connecting exercise with changes in cognitive function, including DNA methylation, histone modifications and microRNAs (miRNAs). The understanding of how exercise promotes long-term cognitive effects is crucial for directing the power of exercise to reduce the burden of neurological and psychiatric disorders.

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“…38 Dysregulation of G9a and/or GLP has been implicated in many human diseases such as cancer, inflammatory diseases, and neurogenerative disorder. 4,6,32,37,39,40 …”

Section: Introductionmentioning

confidence: 99%

Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase

Xiong

Babault

et al. 2017

J. Med. Chem.

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G9a-like protein (GLP) and G9a are highly homologous protein lysine methyltransferases (PKMTs) sharing approximately 80% sequence identity in their catalytic domains. GLP and G9a form a heterodimer complex and catalyze mono- and dimethylation of histone H3 lysine 9 and nonhistone substrates. Although they are closely related, GLP and G9a possess distinct physiological and pathophysiological functions. Thus, GLP or G9a selective small-molecule inhibitors are useful tools to dissect their distinct biological functions. We previously reported potent and selective G9a/GLP dual inhibitors including UNC0638 and UNC0642. Here we report the discovery of potent and selective GLP inhibitors including 4 (MS0124) and 18 (MS012), which are >30-fold and 140-fold selective for GLP over G9a and other methyltransferases, respectively. The cocrystal structures of GLP and G9a in the complex with either 4 or 18 displayed virtually identical binding modes and interactions, highlighting the challenges in structure-based design of selective inhibitors for either enzyme.

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The role of chromatin repressive marks in cognition and disease: A focus on the repressive complex GLP/G9a

Cited by 49 publications

References 113 publications

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Haploinsufficiency of EHMT1 improves pattern separation and increases hippocampal cell proliferation

Physical exercise as an epigenetic modulator of brain plasticity and cognition

Discovery of Potent and Selective Inhibitors for G9a-Like Protein (GLP) Lysine Methyltransferase

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