The prima donna of epigenetics: the regulation of gene expression by DNA methylation

Santos, Kelly Ferreira dos; Mazzola, Taís Nitsch; Carvalho, Hernandes F.

doi:10.1590/s0100-879x2005001000010

Cited by 66 publications

(34 citation statements)

References 54 publications

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“…Methylation, a covalent chemical modification of DNA, is catalyzed by DNA (cytosine-5) methyltransferases (DNMTs) and, together with other modifications affecting chromatin structure, DNA methylation serves to regulate gene transcription. DNA methylation has been studied extensively in development, and has long been considered a static process following cell differentiation (Santos et al, 2005). However, high DNMT mRNA levels persist into adulthood in the brain and we have found that DNMT inhibition alters gene methylation in vitro and in vivo and prevents the induction of LTP and the consolidation of memory (Levenson et al, 2006;Miller and Sweatt, 2007).…”

mentioning

confidence: 69%

DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity

Miller

Campbell

Sweatt

2008

Neurobiology of Learning and Memory

384

359

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A clear understanding is developing concerning the importance of epigenetic-related molecular mechanisms in transcription-dependent long-term memory formation. Chromatin modification, in particular histone acetylation, is associated with transcriptional activation, and acetylation of histone 3 (H3) occurs in Area CA1 of the hippocampus following contextual fear conditioning training. Conversely, DNA methylation is associated with transcriptional repression, but is also dynamically regulated in Area CA1 following training. We recently reported that inhibition of the enzyme responsible for DNA methylation, DNA methyltransferase (DNMT), in the adult rat hippocampus blocks behavioral memory formation. Here we report that DNMT inhibition also blocks the concomitant memory-associated H3 acetylation, without affecting phosphorylation of its upstream regulator, extracellular signal-regulated kinase (ERK). Interestingly, the DNMT inhibitor-induced deficit in memory consolidation, along with deficits in long-term potentiation, can be rescued by pharmacologically increasing levels of histone acetylation prior to DNMT inhibition. These observations suggest that DNMT activity is not only necessary for memory and plasticity, but that DNA methylation may work in concert with histone modifications to regulate plasticity and memory formation in the adult rat hippocampus.

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mentioning

confidence: 69%

DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity

Miller

Campbell

Sweatt

2008

Neurobiology of Learning and Memory

384

359

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“…The more restricted transgene expression in adult mice possibly reflects differences in gene regulation between embryonic and adult tissues. 39 To confirm that it was the Ϫ5.5HS that conferred EC specificity to the 6-kb hEPCR promoter, Ϫ5.5HS was coupled to the heterologous SV40P. In transgenic embryos, high-level reporter gene expression was reproducibly directed to ECs, demonstrating that, by itself, the Ϫ5.5HS enhancer contains the regulatory sequences necessary to impart vascular specificity and thus functions as an autonomous EC-specific enhancer.…”

Section: Discussionmentioning

confidence: 98%

Role of a 5′-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene

Mollica

Crawley

Liu

et al. 2006

Blood

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The endothelial cell protein C receptor (EPCR) is expressed by endothelial cells of large blood vessels and by hematopoietic stem cells. DNaseI hypersensitive (DH) site mapping across 38 kb of the human EPCR gene (hEPCR) locus identified 3 potential regulatory elements. By itself, the DH region spanning the proximal promoter (PP) was unable to direct cell-specific transcription in transgenic mice. A second DH element, located upstream of PP and termed ؊5.5HS was hypersensitive only in endothelial cells (ECs) and immature hematopoietic cell lines. Transgenes expressing LacZ under the control of ؊5.5HS coupled to either PP or the SV40 promoter were able to direct ␤-galactosidase activity to the endothelium of large vessels during embryogenesis and adulthood. The ؊5.5HS exhibited enhancer activity that was conferred by the interplay of transcription factors interacting with conserved Ets and composite GATA/Tal1 motifs. The third DH element, located in intron 2, was primarily hypersensitive in EPCR-negative cells, and capable of initiating antisense transcription, suggesting a role in hEPCR silencing. This study identifies critical elements required for the tissue specificity of hEPCR and suggests a mechanism for endothelial and hematopoietic stem cell-specific transcriptional regulation that reflects the common origin of these cell types. IntroductionThe protein C (PC) anticoagulant pathway plays a crucial role in the regulation of blood coagulation and inflammation. 1 Activated PC (APC) generated in this pathway serves to confine the hemostatic plug to the site of vascular injury by inhibiting the cofactor function of clotting factors Va and VIIIa on intact endothelium. In addition, APC may also exert antiapoptotic and neuroprotective functions that influence inflammatory responses. 2,3 The important regulatory roles of APC in coagulation and inflammation are illustrated by the increased risk of thrombosis incurred by individuals with deficiencies in components of the PC pathway 4 and by the improved outcome of patients with severe sepsis treated with APC. 5 PC is activated by thrombin, but only when thrombin is bound to its receptor, thrombomodulin, present on endothelial cells (ECs). Activation is further enhanced by another EC receptor, the endothelial cell protein C receptor (EPCR). 6 By binding PC, EPCR helps present PC to the thrombin:thrombomodulin complex and so reduces the K m for PC activation. 7 In this way, EPCR enhances APC generation by at least 5-fold in vitro. 7,8 In vivo, blocking protein C-EPCR interactions results in an 88% decrease in circulating APC levels generated in response to thrombin infusion. 9 EPCR function is critical for embryo development because EPCR knockout mice die in midgestation. 10 The normal distribution of EPCR is highly tissue specific. During embryogenesis, EPCR is expressed by the embryonic giant trophoblast cells from approximately E7.5, and by certain embryonic EC from approximately E11.5. 11 In adults, EPCR is expressed almost exclusively by ECs, particularly those o...

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“…Methylation of cytosine nucleotides on DNA itself is the so-called 'fifth-base' of DNA and the 'prima donna' of the epigenetic landscape (Santos et al, 2005). This modification is catalyzed by DNA methyltransferases (DNMTs), which are divided into two groups (see Figure 2).…”

Section: Methylation and Demethylationmentioning

confidence: 99%

Epigenetic Treatments for Cognitive Impairments

Day

Sweatt

2011

Neuropsychopharmacol

109

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Epigenetic mechanisms integrate signals from diverse intracellular transduction cascades and in turn regulate genetic readout. Accumulating evidence has revealed that these mechanisms are critical components of ongoing physiology and function in the adult nervous system, and are essential for many cognitive processes, including learning and memory. Moreover, a number of psychiatric disorders and syndromes that involve cognitive impairments are associated with altered epigenetic function. In this review, we will examine how epigenetic mechanisms contribute to cognition, consider how changes in these mechanisms may lead to cognitive impairments in a range of disorders and discuss the potential utility of therapeutic treatments that target epigenetic machinery. Finally, we will comment on a number of caveats associated with interpreting epigenetic changes and using epigenetic treatments, and suggest future directions for research in this area that will expand our understanding of the epigenetic changes underlying cognitive disorders.

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The prima donna of epigenetics: the regulation of gene expression by DNA methylation

Cited by 66 publications

References 54 publications

DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity

DNA methylation and histone acetylation work in concert to regulate memory formation and synaptic plasticity

Role of a 5′-enhancer in the transcriptional regulation of the human endothelial cell protein C receptor gene

Epigenetic Treatments for Cognitive Impairments

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