A model for mitotic inheritance of histone lysine methylation

Graduate Program, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
EMBO Reports (Impact Factor: 9.06). 11/2011; 13(1):60-7. DOI: 10.1038/embor.2011.206
Source: PubMed


Histone lysine methylation has been implicated in epigenetic regulation of transcription. Using stable-isotope labelling and quantitative mass spectrometry, we analysed the dynamics of histone lysine methylation. Here we report that histone methylation levels are transiently reduced during S phase and are gradually re-established during subsequent cell cycle stages. However, despite the recovery of overall methylation levels before the next S phase, the methylation levels of parental and newly incorporated histones differ significantly. In addition, histone methylation levels are maintained at steady states by both restriction of methyltransferase activity and the active turnover of methyl groups in cells undergoing an extended G1/S phase arrest. Finally, we propose a 'buffer model' that unifies the imprecise inheritance of histone methylation and the faithful maintenance of underlying gene silencing.

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Available from: She Chen, Jan 11, 2015
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    • "We used primary human TIG-3 fibroblasts to compare histone methylation levels in proliferating and G0-arrested cells (Fig. 4B; Supplemental Fig. S7C). H3K9 methylation did not accumulate further in G0-arrested cells, suggesting that accumulation of this modification requires an S-phase arrest as previously reported (Di Micco et al. 2011; Xu et al. 2012). However, for several other methylation marks, including H3K27me2/3, H3K79me1/me2, and H4K20me2/me3, withdrawal from the cell cycle was indeed accompanied by a significant increase (Fig. 4B; Supplemental Fig. S7D). "
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    ABSTRACT: Epigenetic states defined by chromatin can be maintained through mitotic cell division. However, it remains unknown how histone-based information is transmitted. Here we combine nascent chromatin capture (NCC) and triple-SILAC (stable isotope labeling with amino acids in cell culture) labeling to track histone modifications and histone variants during DNA replication and across the cell cycle. We show that post-translational modifications (PTMs) are transmitted with parental histones to newly replicated DNA. Di- and trimethylation marks are diluted twofold upon DNA replication, as a consequence of new histone deposition. Importantly, within one cell cycle, all PTMs are restored. In general, new histones are modified to mirror the parental histones. However, H3K9 trimethylation (H3K9me3) and H3K27me3 are propagated by continuous modification of parental and new histones because the establishment of these marks extends over several cell generations. Together, our results reveal how histone marks propagate and demonstrate that chromatin states oscillate within the cell cycle.
    Genes & Development 03/2015; 29(6):585. DOI:10.1101/gad.256354 · 10.80 Impact Factor
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    • "Thus one should consider that in Drosophila either H3K27me3 was lost through degradation or catalytic demethylation during the recycling of parental histones, or simply fell below the detection limit of the employed assay conditions. Finally, other studies demonstrate that H3K27me3 and even H3K9me3 replenishment occurs gradually through the cell cycle, completing its reestablishment at post-mitotic G1 phase [57] [65] [66]. Thus, there is still some debate concerning the exact fate of these modifications during and after replication, and a careful examination under similar experimental conditions in different organisms is needed to clarify the issue. "
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    ABSTRACT: In eukaryotic organisms, the replication of the DNA sequence and its organization into chromatin is critical to maintain genome integrity. Chromatin components, such as histone variants and histone post-translational modifications, along with the higher-order chromatin structure, impact several DNA metabolic processes, including replication, transcription, and repair. In this review we focus on lysine methylation and the relationships between this histone mark and chromatin replication. We first describe studies implicating lysine methylation in regulating early steps in the replication process. We then discuss chromatin reassembly following replication fork passage, where the incorporation of a combination of newly synthesized histones and parental histones can impact the inheritance of lysine methylation marks on the daughter strands. Finally, we elaborate on how the inheritance of lysine methylation can impact maintenance of the chromatin landscape, using heterochromatin as a model chromatin domain, and we discuss the potential mechanisms involved in this process. This article is part of a Special Issue entitled: Methylation Multifaceted Modification - looking at transcription and beyond, edited by Dr. Johnathan Whetstine.
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 12/2014; DOI:10.1016/j.bbagrm.2014.03.009 · 6.33 Impact Factor
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    • "Histone maturation Some histone marks, such as H3K9 dimethylation reach similar levels in new histones as those in old histones shortly after S phase, suggesting a replication-dependent mechanism (Xu et al, 2012). However, other modifications such as H4K20, and H3K79 methylation, as well as H3K9 and H3K27 trimethylation, are gradually restored throughout the cell cycle, independent of replication (Pesavento et al, 2008; Sweet et al, 2010; Xu et al, 2012). This gradual 'maturation' of histone methylation suggests that epigenetic inheritance is not a rigid process, and its inexact fidelity provides a certain degree of epigenomic flexibility to adapt to changing conditions. "
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    ABSTRACT: Epigenetic regulation of cellular identity and function is at least partly achieved through changes in covalent modifications on DNA and histones. Much progress has been made in recent years to understand how these covalent modifications affect cell identity and function. Despite the advances, whether and how epigenetic factors contribute to memory formation is still poorly understood. In this review, we discuss recent progress in elucidating epigenetic mechanisms of learning and memory, primarily at the DNA level, and look ahead to discuss their potential implications in reward memory and development of drug addiction.
    The EMBO Journal 05/2014; 33(10). DOI:10.1002/embj.201488106 · 10.43 Impact Factor
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