ReviewThe role of chromatin repressive marks in cognition and disease: A focus on the repressive complex GLP/G9a
Introduction
The word “epigenetic” is derived from the ancient Greek prefix “ἐπί” (epi-), which means “on top of”, and the Greek word “γένος” (genos), which means “gene” or “race”. The term epigenetics generally refers to a set of heterogeneous cellular mechanisms that finely control gene expression at multiple levels, while leaving the DNA sequence unaltered. At the biochemical level, these mechanisms include DNA methylation of cytosine residues and post-translational modifications (PTM) of histones. All modifications share the same characteristic; they have the capacity to reversibly modulate transcriptional activity while leaving the DNA sequence itself unaffected. This enables dynamic gene transcription patterns in the nucleus in response to environmental or developmental stimuli.
Chromatin is a structure that consists of DNA and histones, whose function is to package DNA into a smaller volume within the nucleus and to control gene expression. Depending on the condensation state, chromatin can be distinguished into euchromatin and heterochromatin. Euchromatin is the decondensed form, which is associated with genomic regions that are transcriptionally permissive, whereas heterochromatin is compacted and can exist in two forms; (i) facultative, which is actively involved in gene expression and (ii) constitutive, which is obligatorily silenced. The histone protein is the core structure of the nucleosome. Each nucleosome consists of 147–164 base pairs of DNA wrapped around an octamer of histone proteins, which includes two copies of histone H2A, H2B, H3 and H4 each (reviewed by Felsenfeld and Groudine (2003)). Of these proteins, histone 3 (H3) is the most extensively modified. Histone tails protrude out of the nucleosome and these are the areas that are typically accessible for the chemical modifications, such as acetylation, methylation, phosphorylation, ubiquitination, sumoylation, ADP-ribosylation, and others (Cedar and Bergman, 2009, Rose and Klose, 2014, Rothbart and Strahl, 2014). These modifications can be placed by writer enzymes, such as histone acetyltransferases (HATs) and histone methyltransferases (HMTs); removed by eraser enzymes, such as histone deacetylases (HDACs) and histone demethylases (HDMs); and interpreted by reader enzymes, proteins that bind specific chromatin marks or are found in transcription repressor and activator complexes that regulate DNA accessibility by the basic transcription machinery (Kleefstra et al., 2014, Ronan et al., 2013). Writer, eraser and reader enzymes specifically target one or a few modifications. For example, the writer enzyme Euchromatic histone methyltransferase-1 (EHMT1) catalyzes histone 3 lysine 9 (H3K9) mono-and dimethylation, but not trimethylation (Tachibana et al., 2005). The combinatorial nature of histone PTMs impact on gene expression has been postulated to generate a histone code which cells use as an “epigenetic “memory” of previous transcriptional states, yet this model is still under debate (Comoglio and Paro, 2014, de Pretis and Pelizzola, 2014, Lesne et al., 2015, Rando, 2012).
Recently, numerous studies have implicated dynamic changes in DNA methylation and histone PTMs in the formation or consolidation of long-term memories in specific memory-related brain regions. In addition, pathways up and downstream of the chromatin modifying enzymes were found to be part of the signaling pathways governing synaptic plasticity and long-term behavioral memory (Day and Sweatt, 2011a, Day and Sweatt, 2011b, Kramer, 2013, Levenson and Sweatt, 2005, Lipsky, 2013). Consequently, disturbances in epigenetic profiles can impede plasticity and underlie cognitive disorders (Barco, 2014, Kleefstra et al., 2014, Schaefer et al., 2011).
Most of the studies on epigenetics in cognition have focused on DNA methylation and histone H3 (de-)acetylation and have been summarized in excellent recent reviews (Gräff and Mansuy, 2008, Gräff et al., 2012b, Miller et al., 2010, Penney and Tsai, 2014, Zovkic et al., 2013). While DNA methylation is generally considered to inhibit gene transcription and histone acetylation is considered to be activating, histone methylation can achieve both gene activation and repression. Histone methylation initially received less attention, because it was long assumed to be rigid and therefore of little interest to dynamic processes involved in cognition, such as learning and memory. Because the half-life of histone methylation is as long as the histone protein itself [reviewed by Bannister, Schneider, and Kouzarides (2002)], demethylation was thought to happen only passively through cell division. However the discovery of an ‘eraser’ enzyme that removes histone methylation, histone demethylase LSD1 (Shi et al., 2004), suggested that histone methylation could also be dynamically regulated. In general the outcome of histone methylation depends on (a) the type of amino acid being modified, arginine (R) or lysine (K); (b) the extent of methylation (mono-, di- or trimethylation), and (c) the location of the modified residue on the histone tail. In particular, histone H3 methylation has been showed to modulate enduring changes in gene expression to regulate memory formation and neural plasticity (Fischer et al., 2007, Gräff and Mansuy, 2008, Gupta et al., 2010, Gupta-Agarwal et al., 2014, Gupta-Agarwal et al., 2012, Lubin et al., 2011, Parkel et al., 2013).In this review, we focus in particular on Histone H3 Lysine 9 dimethylation (H3K9me2) and on the question how repression of gene transcription controls functional aspects of the nervous system, including: (1) cognition, (2) addiction, and (3) disorders such as intellectual disability (ID) and neurodegeneration, in which the repression of gene transcription has been implied to play a role.
Section snippets
The repressive complex GLP/G9a
Dimethylation of lysine 9 of histone H3 (H3K9me2) is a post-translational modification typically present in both euchromatin and heterochromatin at the promoters of silenced genes. H3K9me2 in euchromatic regions is catalyzed by the heterodimerization of GLP (KMT1D or EHMT1) with G9a (KMT1C or EHMT2) (Tachibana et al., 2002). Indeed chemical inhibitors or genetic manipulations of either GLP or G9a has shown (in vivo and in vitro) to reduce H3K9me2 levels via specific GLP/G9a inhibition of
H3K9 methylation in learning and memory
In recent years, numerous studies have provided evidence that changes in histone lysine methylation, leading to gene expression activation or repression, are also required for the formation and consolidation of long-term memory (LTM) in particular brain regions. Specifically, the expression of H3K4me3 and H3K9me2 marks were found to be transiently and dynamically regulated in rat CA1 hippocampus, entorhinal cortex (EC) and lateral amygdala (LA) following contextual fear-conditioning, a form of
Interference of histone methylation and addiction
Chronic consumption of “recreational” drugs, such as cocaine can lead to devastating psychiatric effects, which are caused by long-lasting changes in the brain’s dopaminergic reward system. One well-characterized reward brain-system affected by cocaine intake is the Ventral-Tegmental Area (VTA) and NAc axis. The VTA projects dopaminergic afferents to the NAc. Cocaine acts as a dopamine reuptake inhibitor (Rothman, 1990) increasing neuronal activity in the NAc. In recent years, numerous studies
GLP/G9A in cognitive disorders
Defects in epigenetic mechanisms may contribute to the development of several cognitive disorders. Many of these disorders involve, among others, memory impairment, learning deficits and neurodevelopmental delays (Barco, 2014, Kelly et al., 2010, Kleefstra et al., 2014, Peña et al., 2014, Portela and Esteller, 2010). Intellectual disability (ID) is a common neurodevelopmental disorder arising before the age of 18 that affects approximately 1–3% of the population. ID is defined by an
Concluding remarks and future perspectives
In this review we highlighted the function of the GLP/G9a repressor complex in cellular processes involved in learning and memory, addiction and disease. Throughout the different studies a picture emerges in which the repressive complex drives both, stable and dynamic repression. The associated H3K9me2 repressive mark can be seen as a “switching” chromatin signal, which recruits players like readers, writers and erasers enzymes. It could act either as a gateway to modulate gene expression
Acknowledgments
The research of the authors is supported by Grants from the “Donders Center for Neuroscience fellowship award of the Radboudumc” [to N.N.K.]; the “FP7-Marie Curie International Reintegration Grant” [to N.N.K. Grant number 277091]; the Jerome Lejeune Foundation [to N.N.K] and GENCODYS, an EU FP7 large-scale integrating project grant [Grant number 241995] [to HvB].
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2021, Neurobiology of Learning and MemoryCitation Excerpt :While histone acetylation is a permissive transcriptional mark, changes in lysine methylation of histones are associated with either activation or repression of gene expression, depending on the location of methylated residue and, for a single lysine residue, the degree of methylation status. In recent years, dimethylation of histone H3 lysine 9 (H3K9me2), a repressive mark catalyzed by histone methyltransferases (HMT) G9a (also known as Ehmt2) and G9a-like protein (GLP, also known as Ehmt1), has emerged as a critical epigenetic regulator of HPC-dependent LTM formation and long-lasting forms of synaptic plasticity (for review, see (Benevento, van de Molengraft, van Westen, van Bokhoven, & Kasri, 2015; Pang, Sharma, & Sajikumar, 2019). Several studies have reported, for example, a pivotal role for G9a/GLP-mediated H3K9me2 in mediating transcriptional homeostasis between gene activation and silencing in area CA1 of the dHPC (dCA1) and the entorhinal cortex during contextual fear memory consolidation (Gupta et al., 2010; Gupta-Agarwal et al., 2012; Mahan et al., 2012).
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2020, Stem Cell ReportsCitation Excerpt :The genome-wide and locus-specific abundance of chromatin marks is determined by counteracting enzymatic activities, such as histone methyltransferases and demethylases (Black et al., 2012). Histone 3 at lysine 9 (H3K9) methylation is an epigenetic mark predominantly associated with gene repression that is conserved during evolution and plays important regulatory functions during embryonic development, sex determination, neuronal plasticity, immune cell function, and tumorigenesis (Benevento et al., 2015; Casciello et al., 2015; Kuroki and Tachibana, 2018; Scheer and Zaph, 2017). H3K9 trimethylation in heterochromatic regions is established by SETDB1 and SUV39H1/2 (Kang, 2015; Peters et al., 2001; Rice et al., 2003), while the H3K9 mono- and dimethyltransferases EHMT1 and EHMT2 (also known as GLP and G9A, respectively) mediate gene silencing at euchromatic loci (Shinkai and Tachibana, 2011).
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2020, BiochimieCitation Excerpt :In addition, G9a methylate several non-histone proteins including p53, a tumor suppressor protein, which is inactivated by G9a mediated methylation [2,3]. The functions of G9a are implicated in the serine metabolism [4], Prader–Willi syndrome [5], maintenance of HIV-1 latency [6], colitis [7], intellectual disabilities and cognitive disturbances (mental retardation, memory formation, age-related cognitive decline, cocaine addiction) [8], embryonic development [9], and cellular reprogramming to produce inducible pluripotent stem cells (iPSCs) [10]. Up-regulation of G9a was reported in various cancers which are associated with metastasis and poor prognosis [11–13].