Fast signals and slow marks: the dynamics of histone modifications

Barth, Teresa K.; Imhof, Axel

doi:10.1016/j.tibs.2010.05.006

Cited by 283 publications

(233 citation statements)

References 77 publications

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“…The activity of promoters is partially defined by the state of histone acetylation and methylation. Hyper-acetylated histones are linked to transcriptionally active domains, whereas hypo-acetylated histones are generally associated with transcriptionally silent domains (33)(34)(35). Therefore we examined these epigenetic signatures in response to hormone exposure utilizing ChIP on the uterine Mcm2 chromatin 3 h after hormone treatment.…”

Section: Resultsmentioning

confidence: 99%

KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing

Ray

Pollard²

2012

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

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In the epithelial compartment of the uterus, estradiol-17β (E 2 ) induces cell proliferation while progesterone (P 4 ) inhibits this response and causes differentiation of the cells. In this study, we identified the mechanism whereby E 2 and P 4 reciprocally regulate the expression of minichromosome maintenance (MCM)-2, a protein that is an essential component of the hexameric MCM-2 to 7 complex required for DNA synthesis initiation. We show in the uterine epithelium that Kruppel-like transcription (KLF) factors, KLF 4 and 15, are inversely expressed; most importantly, they bind to the Mcm2 promoter under the regulation of E 2 and P 4 E 2 , respectively. After P 4 E 2 exposure and in contrast to E 2 treated mice, the Mcm2 promoter displays increased histone 3 (H3) methylation and the recruitment of histone deacetylase 1 and 3 with the concomitant deacetylation of H3. This increased methylation and decreased acetylation is associated with an inhibition of RNA polymerase II binding, indicating an inactive Mcm2 promoter following P 4 E 2 treatment. Using transient transfection assays in the Ishikawa endometrial cell line, we demonstrate that Mcm2 promoter activity is hormonally stimulated by E 2 and that KLF15 inhibits this E 2 enhanced transcription. KLF15 expression also blocks Ishikawa cell proliferation through inhibition of MCM2 protein level. Importantly, in vivo expression of KLF15 in an estrogenized uterus mimics P 4 's action by inhibiting E 2 -induced uterine epithelial MCM-2 expression and DNA synthesis. KLF15 is therefore a downstream physiological mediator of progesterone's cell cycle inhibitory action in the uterine epithelium.endometrium | implantation | menstrual cycle | endometriosis E stradiol-17β (E 2 ) and progesterone (P 4 ) directs uterine preparation for pregnancy. These hormones synthesized cyclically in humans cause a sequential series of proliferative and differentiation events in the uterine stroma and epithelium that result in the epithelium being receptive to the blastocyst for attachment and subsequent implantation (1). Despite this close control of uterine cell proliferation, aberrant proliferative conditions of the human endometrium are common. For example, endometrial polyps and endometriosis are caused by inappropriate proliferation of the uterus, while unopposed estrogen stimulation is associated with menstrual irregularities and endometrial hyperplasia/adenocarcinoma (2). Endometrial cancer is the most common female genital tract malignancy and is responsible for 6% of cancer deaths of women in the United States and more worldwide (3). However, the molecular mechanisms underlying these pathologies are still obscure, as are the molecular mechanisms involved in normal hormonal regulation of cell proliferation in the endometrium, which is essential for successful pregnancy (4).The mouse uterus provides a unique in vivo model to study the regulation of epithelial cell proliferation as the physiological actions of E 2 and P 4 E 2 can be recapitulated in ovariectomized animals by treat...

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Section: Resultsmentioning

confidence: 99%

KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing

Ray

Pollard²

2012

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

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“…Current results indicated that histone lysine methylations in general have a much longer half-life than acetylation or phosphorylation [51,60,61], and that certain methylation states might be established on newly deposited histones in a chromatin assembly-coupled way. But clearly, modification states like H4K20me2 are established by a mechanism independent of DNA replication [51,52].…”

Section: Replication-independent Modification "Maturation" On Newly Dmentioning

confidence: 93%

“…Surprisingly, old H3 histones continue to be methylated at K79 at a rate comparable to that of newly deposited H3 histones, a clear indication that H3K79 methylation cannot be reestablished in a replicationcoupled manner. Given that H3K79me2 shares a similar half-life with the histone modifications most likely to carry epigenetic information (H3K27me3 and H3K9me3) [60,61], it was proposed that there might be a certain degree of positional "scrambling" of K79 methylation through the cell cycle [59].…”

Section: Replication-independent Modification "Maturation" On Newly Dmentioning

confidence: 99%

Epigenetic inheritance: Uncontested?

Reinberg

2011

Cell Res

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"Epigenetics" is currently defined as "the inheritance of variation (-genetics) above and beyond (epi-) changes in the DNA sequence". Despite the fact that histones are believed to carry important epigenetic information, little is known about the molecular mechanisms of the inheritance of histone-based epigenetic information, including histone modifications and histone variants. Here we review recent progress and discuss potential models for the mitotic inheritance of histone modifications-based epigenetic information.

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“…However, as both epigenetic spreading and chromatin dynamics may occur on comparable and relatively fast timescales in vivo (minutes to hours [20,68]), it is extremely difficult to design an experiment to demonstrate this coupling dynamically inside the cell. Here, instead, we proposed, and investigated in silico, a set-up for an experiment to test and quantify the coupling directly in vitro.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic Transitions and Knotted Solitons in Stretched Chromatin

Michieletto

Orlandini

Marenduzzo

2017

Preprint

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The spreading and regulation of epigenetic marks on chromosomes is crucial to establish and maintain cellular identity. Nonetheless, the dynamical mechanism leading to the establishment and maintenance of a given, cell-line specific, epigenetic pattern is still poorly understood. In this work we propose, and investigate in silico, a possible experimental strategy to illuminate the interplay between 3D chromatin structure and epigenetic dynamics. We consider a set-up where a reconstituted chromatin fibre is stretched at its two ends (e.g., by laser tweezers), while epigenetic enzymes (writers) and chromatin-binding proteins (readers) are flooded into the system. We show that, by tuning the stretching force and the binding affinity of the readers for chromatin, the fibre undergoes a sharp transition between a stretched, epigenetically disordered, state and a crumpled, epigenetically coherent, one. We further investigate the case in which a knot is tied along the chromatin fibre, and find that the knotted segment enhances local epigenetic order, giving rise to "epigenetic solitons" which travel and diffuse along chromatin. Our results point to an intriguing coupling between 3D chromatin topology and epigenetic dynamics, which may be investigated via single molecule experiments.

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Fast signals and slow marks: the dynamics of histone modifications

Cited by 283 publications

References 77 publications

KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing

KLF15 negatively regulates estrogen-induced epithelial cell proliferation by inhibition of DNA replication licensing

Epigenetic inheritance: Uncontested?

Epigenetic Transitions and Knotted Solitons in Stretched Chromatin

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