Open Chromatin, Epigenetic Plasticity, and Nuclear Organization in Pluripotency

Schlesinger, S. P.; Meshorer, Eran

doi:10.1016/j.devcel.2019.01.003

Cited by 85 publications

(76 citation statements)

References 142 publications

(210 reference statements)

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“…In previous studies, an open and “hyperdynamic” chromatin conformation has been identified as a general feature of stem cells with chromosomal proteins exchanging more rapidly than in somatic cells . mESCs represent a well‐established reference system for this type of increased chromatin plasticity in comparison to neural progenitor cells derived from them .…”

Section: Resultsmentioning

confidence: 99%

“…Here, we investigated chromatin features associated with the stem cell‐like state of GICs. It was shown previously that an increased plastic and open chromatin state was linked to pluripotency and the self‐renewal potential of mouse and human embryonic stem cells (mESCs/hESCs) . The chromatin distribution in the nucleus of these stem cells was more homogeneous and chromosomal proteins displayed an increased mobility than the corresponding differentiated cells.…”

Section: Introductionmentioning

confidence: 94%

“…In previous studies, an open and "hyperdynamic" chromatin conformation has been identified as a general feature of stem cells with chromosomal proteins exchanging more rapidly than in somatic cells. 11,32,33 mESCs represent a well-established reference system for this type of increased chromatin plasticity in comparison to neural progenitor cells derived from them. 13,34 Consistent with these previous studies, we found that heterochromatin protein 1 alpha (HP1α) as well as the histone methylase SUV39H1 that sets the H3K9me3 mark displayed increased dynamics in their chromatin interactions in mESCs ( Supplementary Fig.…”

Section: Gics Have An Open Chromatin Structurementioning

confidence: 99%

“…It was shown previously that an increased plastic and open chromatin state was linked to pluripotency and the self-renewal potential of mouse and human embryonic stem cells (mESCs/hESCs). 10,11 The chromatin distribution in the nucleus of these stem cells was more homogeneous and chromosomal proteins displayed an increased mobility than the corresponding differentiated cells. In addition, specific patterns of epigenetic modifications were observed that include a global decrease of histone H3 lysine 9 trimethylation (H3K9me3) [12][13][14][15] while H3K9 acetylation, a signature of open chromatin, was increased in human ESCs.…”

Section: Introductionmentioning

confidence: 98%

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Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

Mallm

Windisch

Biran

et al. 2019

Intl Journal of Cancer

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Tumor‐initiating cells are a subpopulation of cells that have self‐renewal capacity to regenerate a tumor. Here, we identify stem cell‐like chromatin features in human glioblastoma initiating cells (GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DNA damage response genes. Upon knockdown of histone demethylases, KDM4C and KDM7A both differentiation and DNA damage were induced. Thus, the H3K9me3–H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Gics Have An Open Chromatin Structurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

Mallm

Windisch

Biran

et al. 2019

Intl Journal of Cancer

Self Cite

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“…Eomes and Brachyury, the exact molecular mechanisms are just starting to be explored [58][59][60][61][62] . Previous reports have suggested that pluripotent cells have globally open chromatin that becomes progressively restricted during differentiation 63 . However, a recent report suggested global differences in chromatin accessibility and methylation patterns between NE and ME gene enhancers in the early pluripotent epiblast 64 .…”

Section: Despite the Wealth Of Knowledge On Transcriptional Regulatiomentioning

confidence: 95%

EomesandBrachyurycontrol pluripotency exit and germ layer segregation by changes of chromatin state

Tošić

Kim

Pavlovic

et al. 2019

Preprint

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The first lineage specification of pluripotent mouse epiblast segregates neuroectoderm (NE) from mesoderm and endoderm (ME) by currently poorly understood mechanisms.Here we demonstrate that the induction of any ME-gene programs critically relies on the T-box (Tbx) transcription factors Eomes and Brachyury that concomitantly repress pluripotency and NE gene programs. Tbx-deficient cells retain pluripotency and differentiate to NE lineages despite the presence of ME-inducing signals TGFb/Nodal and WNT. Pluripotency and NE gene networks are additionally repressed by Tbx-induced ME factors, demonstrating a remarkable redundancy in program regulation to safeguard mutually exclusive lineage specification. Chromatin analyses revealed that accessibility of ME-gene enhancers depends on Tbx-binding, while NE-gene enhancers are accessible and activation-primed already at pluripotency state. This asymmetry of chromatin landscape thus explains the default differentiation of pluripotent cells to NE in the absence of MEinduction mediated through the activating and repressive functions of early Tbx factors Eomes and Brachyury.

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A Unified Linear Viscoelastic Model of the Cell Nucleus Defines the Mechanical Contributions of Lamins and Chromatin

et al. 2020

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The cell nucleus is constantly subjected to externally applied forces. During metazoan evolution, the nucleus has been optimized to allow physical deformability while protecting the genome under load. Aberrant nucleus mechanics can alter cell migration across narrow spaces in cancer metastasis and immune response and disrupt nucleus mechanosensitivity. Uncovering the mechanical roles of lamins and chromatin is imperative for understanding the implications of physiological forces on cells and nuclei. Lamin‐knockout and ‐rescue fibroblasts and probed nucleus response to physiologically relevant stresses are generated. A minimal viscoelastic model is presented that captures dynamic resistance across different cell types, lamin composition, phosphorylation states, and chromatin condensation. The model is conserved at low and high loading and is validated by micropipette aspiration and nanoindentation rheology. A time scale emerges that separates between dominantly elastic and dominantly viscous regimes. While lamin‐A and lamin‐B1 contribute to nucleus stiffness, viscosity is specified mostly by lamin‐A. Elastic and viscous association of lamin‐B1 and lamin‐A is supported by transcriptional and proteomic profiling analyses. Chromatin decondensation quantified by electron microscopy softens the nucleus unless lamin‐A is expressed. A mechanical framework is provided for assessing nucleus response to applied forces in health and disease.

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Open Chromatin, Epigenetic Plasticity, and Nuclear Organization in Pluripotency

Cited by 85 publications

References 142 publications

Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

Glioblastoma initiating cells are sensitive to histone demethylase inhibition due to epigenetic deregulation

EomesandBrachyurycontrol pluripotency exit and germ layer segregation by changes of chromatin state

A Unified Linear Viscoelastic Model of the Cell Nucleus Defines the Mechanical Contributions of Lamins and Chromatin

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