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1.
Epigenetic mechanisms in mammals 总被引:11,自引:1,他引:10
DNA and histone methylation are linked and subjected to mitotic inheritance in mammals. Yet how methylation is propagated
and maintained between successive cell divisions is not fully understood. A series of enzyme families that can add methylation
marks to cytosine nucleobases, and lysine and arginine amino acid residues has been discovered. Apart from methyltransferases,
there are also histone modification enzymes and accessory proteins, which can facilitate and/or target epigenetic marks. Several
lysine and arginine demethylases have been discovered recently, and the presence of an active DNA demethylase is speculated
in mammalian cells. A mammalian methyl DNA binding protein MBD2 and de novo DNA methyltransferase DNMT3A and DNMT3B are shown experimentally to possess DNA demethylase activity. Thus, complex mammalian
epigenetic mechanisms appear to be dynamic yet reversible along with a well-choreographed set of events that take place during
mammalian development. 相似文献
2.
Even though every cell in a multicellular organism contains the same genes, the differing spatiotemporal expression of these
genes determines the eventual phenotype of a cell. This means that each cell type contains a specific epigenetic program that
needs to be replicated through cell divisions, along with the genome, in order to maintain cell identity. The stable inheritance
of these programs throughout the cell cycle relies on several epigenetic mechanisms. In this review, DNA methylation and histone
methylation by specific histone lysine methyltransferases (KMT) and the Polycomb/Trithorax proteins are considered as the
primary mediators of epigenetic inheritance. In addition, non-coding RNAs and nuclear organization are implicated in the stable
transfer of epigenetic information. Although most epigenetic modifications are reversible in nature, they can be stably maintained
by self-recruitment of modifying protein complexes or maintenance of these complexes or structures through the cell cycle. 相似文献
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A. Shukla P. Chaurasia S. R. Bhaumik 《Cellular and molecular life sciences : CMLS》2009,66(8):1419-1433
Methylation of lysine residues of histones is associated with functionally distinct regions of chromatin, and, therefore,
is an important epigenetic mark. Over the past few years, several enzymes that catalyze this covalent modification on different
lysine residues of histones have been discovered. Intriguingly, histone lysine methylation has also been shown to be cross-regulated
by histone ubiquitination or the enzymes that catalyze this modification. These covalent modifications and their cross-talks
play important roles in regulation of gene expression, heterochromatin formation, genome stability, and cancer. Thus, there
has been a very rapid progress within past several years towards elucidating the molecular basis of histone lysine methylation
and ubiquitination, and their aberrations in human diseases. Here, we discuss these covalent modifications with their cross-regulation
and roles in controlling gene expression and stability.
Received 24 September 2008; received after revision 21 November 2008; accepted 28 November 2008 相似文献
5.
Site- and state-specific lysine methylation of histones is catalyzed by a family of proteins that contain the evolutionarily
conserved SET domain and plays a fundamental role in epigenetic regulation of gene activation and silencing in all eukaryotes.
The recently determined three-dimensional structures of the SET domains from chromosomal proteins reveal that the core SET
domain structure contains a two-domain architecture, consisting of a conserved anti-parallel β-barrel and a structurally variable
insert that surround a unusual knot-like structure that comprises the enzyme active site. These structures of the SET domains,
either in the free state or when bound to cofactor S-adenosyl-L-homocysteine and/or histone peptide, mimicking an enzyme/cofactor/substrate complex, further yield the structural insights
into the molecular basis of the substrate specificity, methylation multiplicity and the catalytic mechanism of histone lysine
methylation.
Received 10 June 2006; accepted 22 August 2006 相似文献
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Zijun Wang Hai Long Christopher Chang Ming Zhao Qianjin Lu 《Cellular and molecular life sciences : CMLS》2018,75(18):3353-3369
Little information is available regarding mechanistic links between epigenetic modifications and autoimmune diseases. It seems plausible to surmise that aberrant gene expression and energy metabolism would disrupt immune tolerance, which could ultimately result in autoimmune responses. Metaboloepigenetics is an emerging paradigm that defines the interrelationships between metabolism and epigenetics. Epigenetic modifications, such as the methylation/demethylation of DNA and histone proteins and histone acetylation/deacetylation can be dynamically produced and eliminated by a group of enzymes that consume several metabolites derived from various physiological pathways. Recent insights into cellular metabolism have demonstrated that environmental stimuli such as dietary exposure and nutritional status act through the variation in concentration of metabolites to affect epigenetic regulation and breakdown biochemical homeostasis. Metabolites, including S-adenosylmethionine, acetyl-CoA, nicotinamide adenine dinucleotide, α-ketoglutarate, and ATP serve as cofactors for chromatin-modifying enzymes, such as methyltransferases, deacetylases and kinases, which are responsible for chromatin remodelling. The concentration of crucial nutrients, such as glucose, glutamine, and oxygen, spatially and temporally modulate epigenetic modifications to regulate gene expression and the reaction to stressful microenvironments in disease pathology. In this review, we focus on the interaction between metabolic intermediates and epigenetic modifications, integrating environmental signals with programmes through modification of the epigenome–metabolome to speculate as to how this may influence autoimmune diseases. 相似文献
8.
Dynamic protein methylation in chromatin biology 总被引:1,自引:1,他引:0
9.
Herrmann A Svangård E Claeson P Gullbo J Bohlin L Göransson U 《Cellular and molecular life sciences : CMLS》2006,63(2):235-245
Cyclotides are cyclic plant proteins with potent cytotoxic effects. Here we systematically probed the importance of surface-exposed
charged amino acid residues of the cyclotide cycloviolacin O2, using a strategy involving chemical modifications. We show
that the single glutamic acid plays a key role for the cytotoxicity: methylation of this residue produced a 48-fold decrease
in potency. Virtually no change in potency was observed when masking the single arginine residue using 1,2-cyclohexanedione,
while acetylation of the two lysine residues reduced the potency 3-fold. The derivative with modifications at both arginine
and lysine residues showed a 7-fold loss of potency. In addition, we show that the activity is dependent on an intact disulfide
network and that the short sequences between the six cysteine residues, that is, the backbone loops, are devoid of cytotoxic
activity.
Received 11 October 2005; received after revision 3 November 2005; accepted 15 November 2005 相似文献
10.
Covadonga Huidobro Agustin F. Fernandez Mario F. Fraga 《Cellular and molecular life sciences : CMLS》2013,70(9):1543-1573
Epigenetic mechanisms play an important role in gene regulation during development. DNA methylation, which is probably the most important and best-studied epigenetic mechanism, can be abnormally regulated in common pathologies, but the origin of altered DNA methylation remains unknown. Recent research suggests that these epigenetic alterations could depend, at least in part, on genetic mutations or polymorphisms in DNA methyltransferases and certain genes encoding enzymes of the one-carbon metabolism pathway. Indeed, the de novo methyltransferase 3B (DNMT3B) has been recently found to be mutated in several types of cancer and in the immunodeficiency, centromeric region instability and facial anomalies syndrome (ICF), in which these mutations could be related to the loss of global DNA methylation. In addition, mutations in glycine-N-methyltransferase (GNMT) could be associated with a higher risk of hepatocellular carcinoma and liver disease due to an unbalanced S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio, which leads to aberrant methylation reactions. Also, genetic variants of chromatin remodeling proteins and histone tail modifiers are involved in genetic disorders like α thalassemia X-linked mental retardation syndrome, CHARGE syndrome, Cockayne syndrome, Rett syndrome, systemic lupus erythematous, Rubinstein–Taybi syndrome, Coffin–Lowry syndrome, Sotos syndrome, and facioescapulohumeral syndrome, among others. Here, we review the potential genetic alterations with a possible role on epigenetic factors and discuss their contribution to human disease. 相似文献
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Dewei Chen Wenxiang Gao Shouxian Wang Bing Ni Yuqi Gao 《Cellular and molecular life sciences : CMLS》2017,74(20):3789-3808
Pulmonary arterial hypertension (PAH) is characterized by persistent pulmonary vasoconstriction and pulmonary vascular remodeling. The pathogenic mechanisms of PAH remain to be fully clarified and measures of effective prevention are lacking. Recent studies; however, have indicated that epigenetic processes may exert pivotal influences on PAH pathogenesis. In this review, we summarize the latest research findings regarding epigenetic regulation in PAH, focusing on the roles of non-coding RNAs, histone modifications, ATP-dependent chromatin remodeling and DNA methylation, and discuss the potential of epigenetic-based therapies for PAH. 相似文献
14.
Silencing of DNA repair genes plays a critical role in the development of the cancer because these genes, functioning normally, would prevent the accumulation of mutations leading to carcinogenesis. Epigenetic gene silencing is an alternative mechanism to genetic gene aberration, inactivating those genes in cancer. DNA methylation and histone modification are the major factors for epigenetic regulation of gene expression. Here, we describe recent advances in understanding of epigenetic silencing of DNA repair genes and their epigenetic mechanisms involving DNA methylation and histone modification. 相似文献
15.
DNA methylation is a stable but not irreversible epigenetic signal that silences gene expression. It has a variety of important functions in mammals, including control of gene expression, cellular differentiation and development, preservation of chromosomal integrity, parental imprinting and X-chromosome inactivation. In addition, it has been implicated in brain function and the development of the immune system. Somatic alterations in genomic methylation patterns contribute to the etiology of human cancers and ageing. It is tightly interwoven with the modification of histone tails and other epigenetic signals. Here we review our current understanding of the molecular enzymology of the mammalian DNA methyltransferases Dnmt1, Dnmt3a, Dnmt3b and Dnmt2 and the roles of the enzymes in the above-mentioned biological processes. 相似文献
16.
DNA methylation and the regulation of gene transcription 总被引:28,自引:0,他引:28
17.
Emerging connections between DNA methylation and histone acetylation 总被引:18,自引:0,他引:18
Modifications of both DNA and chromatin can affect gene expression and lead to gene silencing. Evidence of links between
DNA methylation and histone hypoacetylation is accumulating. Several proteins that specifically bind to methylated DNA are
associated with complexes that include histone deacetylases (HDACs). In addition, DNA methyltransferases of mammals appear
to interact with HDACs. Experiments with animal cells have shown that HDACs are responsible for part of the repressive effect
of DNA methylation. Evidence was found in Neurospora that protein acetylation can in some cases affect DNA methylation. The available data suggest that the roles of DNA methylation
and histone hypoacetylation, and their relationship with each other, can vary, even within an organism. Some open questions
in this emerging field that should be answered in the near future are discussed. 相似文献
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Xiaoming Zhang Wisna Novera Yan Zhang Lih-Wen Deng 《Cellular and molecular life sciences : CMLS》2017,74(13):2333-2344
The mixed lineage leukemia (MLL) family of genes, also known as the lysine N-methyltransferase 2 (KMT2) family, are homologous to the evolutionarily conserved trithorax group that plays critical roles in the regulation of homeotic gene (HOX) expression and embryonic development. MLL5, assigned as KMT2E on the basis of its SET domain homology, was initially categorized under MLL (KMT2) family together with other six SET methyltransferase domain proteins (KMT2A–2D and 2F–2G). However, emerging evidence suggests that MLL5 is distinct from the other MLL (KMT2) family members, and the protein it encodes appears to lack intrinsic histone methyltransferase (HMT) activity towards histone substrates. MLL5 has been reported to play key roles in diverse biological processes, including cell cycle progression, genomic stability maintenance, adult hematopoiesis, and spermatogenesis. Recent studies of MLL5 variants and isoforms and putative MLL5 homologs in other species have enriched our understanding of the role of MLL5 in gene expression regulation, although the mechanism of action and physiological function of MLL5 remains poorly understood. In this review, we summarize recent research characterizing the structural features and biological roles of MLL5, and we highlight the potential implications of MLL5 dysfunction in human disease. 相似文献
20.
Lysyl oxidase: an oxidative enzyme and effector of cell function 总被引:8,自引:1,他引:7
Lysyl oxidase (LOX) oxidizes the side chain of peptidyl lysine converting specific lysine residues to residues of alpha-aminoadipic-delta-semialdehyde. This posttranslational chemical change permits the covalent crosslinking of the component chains of collagen and those of elastin, thus stabilizing the fibrous deposits of these proteins in the extracellular matrix. Four LOX-like (LOXL) proteins with varying degrees of similarity to LOX have been described, constituting a family of related proteins. LOX is synthesized as a preproprotein which emerges from the cell as proLOX and then is processed to the active enzyme by proteolysis. In addition to elastin and collagen, LOX can oxidize lysine within a variety of cationic proteins, suggesting that its functions extend beyond its role in the stabilization of the extracellular matrix. Indeed, recent findings reveal that LOX and LOXL proteins markedly influence cell behavior including chemotactic responses, proliferation, and shifts between the normal and malignant phenotypes. 相似文献