Lsh, a member of the SNF2 family, is required for genome-wide methylation

Dennis, Kathleen E.; Fan, Tao; Geiman, Theresa M.; Yan, Qingsheng; Muegge, Kathrin

doi:10.1101/gad.929101

Cited by 337 publications

(288 citation statements)

References 36 publications

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“…Finally, nucleosome remodeling can affect DNA methylation, as evident from genetic studies in Arabidopsis thaliana, where mutation of the SNF2-like gene DDM1 causes a dramatic decrease in the level of genomic cytosine methylation (Jeddeloh et al 1999). In the mouse, disruption of the Lsh locus encoding the SNF2-like helicase PASG results in genomic demethylation (Dennis et al 2001;Sun et al 2004), demonstrating concerted functionality between nucleosome remodeling and DNA methylation. Lsh deficiency also affects histone methylation patterns at pericentromeric heterochromatin, resulting in the accumulation of methylated Lys 4 of histone H3 and pointing to cross-talk between epigenetic layers of regulation (Yan et al 2003).…”

Section: Integrative Epigenetics: Forces Of Stabilitymentioning

confidence: 99%

Epigenetics and cancer

Lund¹,

Lohuizen²

2004

Genes Dev.

438

312

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Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes. Epigenetic gene regulation collaborates with genetic alterations in cancer development. This is evident from every aspect of tumor biology including cell growth and differentiation, cell cycle control, DNA repair, angiogenesis, migration, and evasion of host immunosurveillance. In contrast to genetic cancer causes, the possibility of reversing epigenetic codes may provide new targets for therapeutic intervention.Epigenetic programming is crucial in mammalian development, and stable inheritance of epigenetic settings is essential for the maintenance of tissue-and cell-typespecific functions (Li 2002). With the exception of controlled genomic rearrangements, such as those of the immunoglobulin and T-cell receptor genes in B and T cells, all other differentiation processes are initiated or maintained through epigenetic processes. Not surprisingly therefore, epigenetic gene regulation is characterized overall by a high degree of integrity and stability. Evidence is accumulating that suggests that the intrinsic stability is caused by multiple interlocking feedback mechanisms between functionally unrelated epigenetic layers, such as DNA methyltransferases (DNMTs) and histone modifying enzymes, resulting in the stable commitment of a locus to a particular activity state. In somatic cells, the transcriptional status of most genes is epigenetically fixed. However, other genes, such as cell cycle checkpoint genes and genes directly affected by exogenous stimuli such as growth factors or cell-cell contact, likely reside in a balanced state sensitive to dynamic adjustments in histone modifications, thereby allowing for rapid responses to specific stimuli. Perturbation of epigenetic balances may lead to alterations in gene expression, ultimately resulting in cellular transformation and malignant outgrowth; the involvement of deregulated epigenetic mechanisms in cancer development has received increased attention in recent years.Per definition, epigenetic regulators alter the activities and abilities of a cell without directly affecting and mutating the sequence of the DNA. In this review, we deal with epigenetic gene regulation as imposed by DNA methylation, covalent modifications of the canonical core histones, deposition of variant histone proteins, local nucleosome remodeling, and long-range epigenetic regulators. Understanding the molecular details behind "epigenetic cancer diseases" holds potentially important prospects for medical treatment, as it allows for novel strategies for drug development. A number of recent reviews have provided details on epigenetic mechanisms and their involvement in cancer, and we refer to these for more in-depth information on individual epigenetic mechanisms

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Section: Integrative Epigenetics: Forces Of Stabilitymentioning

confidence: 99%

Epigenetics and cancer

Lund¹,

Lohuizen²

2004

Genes Dev.

438

312

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“…A fundamental question concerns how a specific sequence is selectively methylated by the de novo enzymes in cells. Evidence for cross-talk between DNA methylation and histone modification has been found in various contexts of transcriptional regulation and chromatin functions [4][5][6][7][8]. In the filamentous fungus Neurospora crassa, either the replacement of histone H3 lysine 9 (H3K9) with other amino acids or deletion of the sole H3K9 methyltransferase DIM5 results in the loss of DNA methylation [9].…”

Section: Introductionmentioning

confidence: 99%

Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase

et al. 2011

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Cytosine methylation of genomic DNA controls gene expression and maintains genome stability. How a specific DNA sequence is targeted for methylation by a methyltransferase is largely unknown. Here, we show that histone H3 tails lacking lysine 4 (K4) methylation function as an allosteric activator for methyltransferase Dnmt3a by binding to its plant homeodomain (PHD). In vitro, histone H3 peptides stimulated the methylation activity of Dnmt3a up to 8-fold, in a manner reversely correlated with the level of K4 methylation. The biological significance of allosteric regulation was manifested by molecular modeling and identification of key residues in both the PHD and the catalytic domain of Dnmt3a whose mutations impaired the stimulation of methylation activity by H3 peptides but not the binding of H3 peptides. Significantly, these mutant Dnmt3a proteins were almost inactive in DNA methylation when expressed in mouse embryonic stem cells while their recruitment to genomic targets was unaltered. We therefore propose a two-step mechanism for de novo DNA methylation -first recruitment of the methyltransferase probably assisted by a chromatin-or DNA-binding factor, and then allosteric activation depending on the interaction between Dnmt3a and the histone tails -the latter might serve as a checkpoint for the methylation activity.

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“…They can exist in macromolecular complexes in combination with other remodellers or with a wide selection of other chromatin proteins including HDACs. (25,61) Mammalian chromatin remodellers have been shown to be essential for DNA methylation (62) and can recruit heterochromatin proteins to newly methylated DNA via an association with methyl CpG-binding proteins. (63) …”

Section: Atp-dependent Chromatin Remodellers and Their Complexesmentioning

confidence: 99%

Heterochromatin?many flavours, common themes

Craig

2004

Bioessays

114

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SummaryHeterochromatin remains condensed throughout the cell cycle, is generally transcriptionally inert and is built and maintained by groups of factors with each group member sharing a similar function. In mammals, these groups include sequence-specific transcriptional repressors, functional RNA and proteins involved in DNA and histone methylation. Heterochromatin is cemented together via interactions within and between each protein group and is maintained by the cell's replication machinery. It can be constitutive (permanent) or facultative (developmentally regulated) and be any size, from a gene promotor to a whole genome. By studying the formation of facultative heterochromatin, we have gained information about how heterochromatin is assembled. We have discovered that there are many different architectural plans for the building of heterochromatin, leading to a seemingly never-ending variety of heterochromatic loci, with each built according to a general rule.

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Lsh, a member of the SNF2 family, is required for genome-wide methylation

Cited by 337 publications

References 36 publications

Epigenetics and cancer

Epigenetics and cancer

Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase

Heterochromatin?many flavours, common themes

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