Restricted epigenetic inheritance of H3K9 methylation

Audergon, Pauline N. C. B.; Catania, Sandra; Kagansky, Alexander; Tong, Pin; Shukla, Manu; Pidoux, Alison L.; Allshire, Robin C.

doi:10.1126/science.1260638

Cited by 242 publications

(285 citation statements)

References 31 publications

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“…3B), suggesting that Lem2 influences the establishment or maintenance of this repressive mark. Epe1 shows homology with histone demethylases and has been reported to affect the stability of H3K9me at ectopic heterochromatic domains (Audergon et al 2015;Ragunathan et al 2015). Thus, it may be conceivable that Lem2 controls H3K9me and silencing at pericentromeres primarily through regulating Epe1.…”

Section: Mechanism Of Lem2-mediated Silencingmentioning

confidence: 99%

Control of heterochromatin localization and silencing by the nuclear membrane protein Lem2

et al. 2016

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Transcriptionally silent chromatin localizes to the nuclear periphery, which provides a special microenvironment for gene repression. A variety of nuclear membrane proteins interact with repressed chromatin, yet the functional role of these interactions remains poorly understood. Here, we show that, in Schizosaccharomyces pombe, the nuclear membrane protein Lem2 associates with chromatin and mediates silencing and heterochromatin localization. Unexpectedly, we found that these functions can be separated and assigned to different structural domains within Lem2, excluding a simple tethering mechanism. Chromatin association and tethering of centromeres to the periphery are mediated by the N-terminal LEM (LAP2-Emerin-MAN1) domain of Lem2, whereas telomere anchoring and heterochromatin silencing require exclusively its conserved C-terminal MSC (MAN1-Src1 C-terminal) domain. Particularly, silencing by Lem2 is epistatic with the Snf2/HDAC (histone deacetylase) repressor complex SHREC at telomeres, while its necessity can be bypassed by deleting Epe1, a JmjC protein with anti-silencing activity. Furthermore, we found that loss of Lem2 reduces heterochromatin association of SHREC, which is accompanied by increased binding of Epe1. This reveals a critical function of Lem2 in coordinating these antagonistic factors at heterochromatin. The distinct silencing and localization functions mediated by Lem2 suggest that these conserved LEM-containing proteins go beyond simple tethering to play active roles in perinuclear silencing.

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Section: Mechanism Of Lem2-mediated Silencingmentioning

confidence: 99%

Control of heterochromatin localization and silencing by the nuclear membrane protein Lem2

et al. 2016

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“…In this way, CG can harbor molecular memory long term using a stable, but malleable, encoding system. In contrast, except following genetic manipulation [13,14], other epigenetic modifications (such as histone methylation or acetylation) do not have an equivalent capacity to maintain specific marks in long term [15]. High levels of CG methylation (70-85%) are found throughout the somatic tissues of humans and mice [16,17].…”

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confidence: 99%

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

Hore

2017

Epigenomics

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Vitamins A and C represent unrelated sets of small molecules that are essential to the human diet and have recently been shown to intensify erasure of epigenetic memory in naive embryonic stem cells. These effects are driven by complementary enhancement of the ten-eleven translocation (TET) demethylases -vitamin A stimulates TET expression, whereas vitamin C potentiates TET catalytic activity. Vitamin A and C cosupplementation synergistically enhances reprogramming of differentiated cells to the naive state, but overuse may exaggerate instability of imprinted genes. As such, optimizing their use in culture media will be important for regenerative medicine and mammalian transgenics. In addition, mechanistic perception of how these vitamins interact with the epigenome may be relevant for understanding cancer and improving patient treatment. Figure 1A), and both are associated with a long recorded history. Nightblindness, an early symptom of vitamin A deficiency, and its cure through liver consumption, was known to Egyptians in the prehistoric period [1]. Equally, the debilitating effects of scurvy (vitamin C deficiency) among sailors, and its treatment with oranges, was registered as far back as 1498 [2]. Vitamins A and C also have a lengthy and rich history in scientific literature; in 1753 James Lind described the first controlled clinical trial where various antiscorbutic treatments were tested on British seamen and in 1929, Frederick Gowland Hopkins was co-awarded the Nobel Prize in Medicine for the 'discovery of vitamins' following milk supplementation experiments in vitamin A deficient mice [3]. Eventual isolation of the respective compounds underlying both vitamins led to Nobel Prizes in Chemistry and Medicine in 1937 [4]. Since this time, a considerable amount of scientific progress (and at times conjecture) has been associated with vitamins A and C, and their respective biological effects touch disciplines as divergent as development and dermatology.One of the most recently discovered fields that vitamins A and C impact upon is epigenetics [5][6][7]. New research has shown that both vitamins drive active removal of DNA methylation in embryonic stem cells (ESCs) by enhancing the same family of ten-eleven translocation (TET) enzymes, and in doing so, help erase DNA methylation and the epigenetic memory encoded by it to improve the reprogramming of differentiated cells to an embryonic-like state. Here I review the effects of vitamins A and C on DNA methylation and epigenetic memory in stem cells, and outline their significance for the fields For reprint orders, please contact: reprints@futuremedicine.com

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“…Transcriptional memory at promoters can be maintained by a number of mechanisms, including DNA methylation (42), histone modification (43,44), localization to the nuclear periphery (45,46), and heterochromatin formation (47,48). Both small RNAs (49,50) and lncRNAs (14,15) can be required for these epigenetic effects.…”

Section: Discussionmentioning

confidence: 99%

Disruption of promoter memory by synthesis of a long noncoding RNA

Yarrington

Chuong

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The yeast HO endonuclease is expressed in late G1 in haploid mother cells to initiate mating-type interconversion. Cells can be arrested in G1 by nutrient deprivation or by pheromone exposure, but cells that resume cycling after nutrient deprivation or cyclindependent kinase (CDK) inactivation express HO in the first cell cycle, whereas HO is not expressed until the second cycle after release from pheromone arrest. Here, we show that transcription of a long noncoding RNA (lncRNA) mediates this differential response. The SBF and Mediator factors remain bound to the inactive promoter during arrest due to CDK inactivation, and these bound factors allow the cell to remember a transcriptional decision made before arrest. If the presence of mating pheromone indicates that this decision is no longer appropriate, a lncRNA originating at -2700 upstream of the HO gene is induced, and the transcription machinery displaces promoter-bound SBF, preventing HO transcription in the subsequent cell cycle. Further, we find that the displaced SBF is blocked from rebinding due to incorporation of its recognition sites within nucleosomes. Expressing the pHO-lncRNA in trans is ineffective, indicating that transcription in cis is required. Factor displacement during lncRNA transcription could be a general mechanism for regulating memory of previous events at promoters.lncRNA | nucleosomes | promoter memory | gene regulation | chromatin

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Restricted epigenetic inheritance of H3K9 methylation

Cited by 242 publications

References 31 publications

Control of heterochromatin localization and silencing by the nuclear membrane protein Lem2

Control of heterochromatin localization and silencing by the nuclear membrane protein Lem2

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

Disruption of promoter memory by synthesis of a long noncoding RNA

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