Histone deacetylase inhibition accelerates the early events of stem cell differentiation: transcriptomic and epigenetic analysis

Karantzali, Efthimia; Schulz, Herbert; Hummel, Oliver; Hübner, Norbert; Hatzopoulos, AK; Kretsovali, Androniki

doi:10.1186/gb-2008-9-4-r65

Cited by 94 publications

(105 citation statements)

References 46 publications

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“…Brief histone hyperacetylation induced by TSA treatment induced nestin expression in P19 EC cells and enhanced proneural and Sox2 neural gene expression when performed at the neural progenitor stage (24). In other contexts, hyperacetylation of chromatin enhances cellular plasticity and facilitates somatic cell reprogramming (32,33). Together, these findings suggest that open and acetylated chromatin is conducive to promoting early and multipotential cell states including neural precursors.…”

Section: Discussionmentioning

confidence: 52%

Geminin promotes neural fate acquisition of embryonic stem cells by maintaining chromatin in an accessible and hyperacetylated state

Yellajoshyula

Patterson

Elitt

et al. 2011

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

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Formation of the complex vertebrate nervous system begins when pluripotent cells of the early embryo are directed to acquire a neural fate. Although cell intrinsic controls play an important role in this process, the molecular nature of this regulation is not well defined. Here we assessed the role for Geminin, a nuclear protein expressed in embryonic cells, during neural fate acquisition from mouse embryonic stem (ES) cells. Whereas Geminin knockdown does not affect the ability of ES cells to maintain or exit pluripotency, we found that it significantly impairs their ability to acquire a neural fate. Conversely, Geminin overexpression promotes neural gene expression, even in the presence of growth factor signaling that antagonizes neural transcriptional responses. These data demonstrate that Geminin's activity contributes to mammalian neural cell fate acquisition. We investigated the mechanistic basis of this phenomenon and found that Geminin maintains a hyperacetylated and open chromatin conformation at neural genes. Interestingly, recombinant Geminin protein also rapidly alters chromatin acetylation and accessibility even when Geminin is combined with nuclear extract and chromatin in vitro. Together, these data support a role for Geminin as a cell intrinsic regulator of neural fate acquisition that promotes expression of neural genes by regulating chromatin accessibility and histone acetylation.

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Section: Discussionmentioning

confidence: 52%

Geminin promotes neural fate acquisition of embryonic stem cells by maintaining chromatin in an accessible and hyperacetylated state

Yellajoshyula

Patterson

Elitt

et al. 2011

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

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“…9 Several studies have shown that patterns of histone modification have been associated with many essential biological processes, such as stem cell maintenance and differentiation. 10,16,21 Previous studies have revealed that mesenchymal stem cells exist in ligamentum flavum and play a crucial role in the development of OLF. 3,18 Whether histone modifications are involved in this ossification process has not been studied.…”

mentioning

confidence: 99%

“…9,10,16,21 After translation of histone proteins, their N-terminal tails are susceptible to a range of covalent modifications, such as acetylation, methylation, phosphorylation, and ubiquitination.…”

mentioning

confidence: 99%

Recombinant human bone morphogenetic protein-2–induced ossification of the ligamentum flavum in rats and the associated global modification of histone H3

Huang

Fan²,

Sun³

et al. 2014

SPI

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Object The primary object of this investigation was to study recombinant human bone morphogenetic protein–2 (rhBMP-2)–induced ossification of the ligamentum flavum and associated histone H3 modification in a rat model. In an additional set of studies the authors investigated spinal cord and behavioral changes in the same model. Methods The authors report on 2 separate sets of studies. A total of 90 rats were used for the 2 sets of studies (45 each); in each study, a lyophilized rhBMP-2 and collagen mixture (20 μg rhBMP-2 and 200 μl collagen) was implanted in the lumbar extradural space in 18 rats; another 18 animals were used for a sham-operation control group and underwent implantation of lyophilized collagen without rhBMP-2 at the same level; an additional 9 animals were used as untreated controls. Lumbar spinal samples were harvested from the rhBMP-2 groups and the shamoperation control groups at 1 week, 3 weeks, and 9 weeks after the operation. Samples were also obtained from untreated controls at the same time points. All samples were scanned using micro-CT and then made into paraffinembedded sections. The sections from the first set of 45 rats were stained using elastica van Gieson and toluidine blue, and the expression of histone modifications (H3K9ac, H3K18ac, H3K4me3, and H3K36me3) and osteogenic transcription factors (osterix, Runx2) was detected by immunohistochemistry. In the second set of studies, hindlimb motor function was assessed at 1 week, 3 weeks, and 9 weeks after surgery. After behavioral evaluation, samples were harvested, scanned using micro-CT, and then made into paraffin-embedded sections. The sections were stained using Luxol fast blue. The expression of NeuN was also detected using immunohistochemistry. Results Ossification was seen in the rhBMP-2 group from 1 week after insertion, and the volume of ossified mass increased at 3 and 9 weeks. There was no ossification seen in the sham-surgery and normal controls. The pathological changes of ossification involved ligament degeneration, cartilage formation, and, finally, bone replacement. Spinal cord evaluation showed a significant decrease in white matter content and number of neurons at 9 weeks after operation in the rhBMP-2–treated group (compared with findings in the sham-surgery and control groups as well as findings at the earlier time points in the rhBMP-2 group). Using immunohistochemical staining, histone modifications (H3K9ac, H3K18ac, H3K4me3, and H3K36me3) and osteogenic transcription factors (osterix, Runx2) all were found to be expressed in the fibrocartilage area of the rat ossified ligamentum flavum samples (rhBMP2 group). Conclusions This rhBMP-2–induced OLF is a typical endochondral ossification, which is similar to clinical OLF. The compressed spinal cord around the ossification site showed signs of a chronic degenerative process. Histone H3 modifications (H3K9ac, H3K18ac, H3K4me3, and H3K36me3) may play an important role in OLF.

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“…Knockdown of the expression of histone deacetylase 1 (Hdac1) in rat mesenchymal stem cells from bone marrow increased the levels of expression of cardiomyocyterelated genes [49]. It has been proposed that the inhibition of histone deacetylase activity downregulates the expression of genes characteristic for the undifferentiated state but upregulates differentiation-associated genes, thus accelerating the onset of differentiation [50]. One of the characteristics of the undifferentiated state is chromatin hyperplasticity, warranting the access of the nuclear transactions machinery to DNA.…”

Section: Cardiomyocytes Produced By Differentiation Ofmentioning

confidence: 99%

We heart cultured hearts. A comparative review of methodologies for targeted differentiation and maintenance of cardiomyocytes derived from pluripotent and multipotent stem cells

Arabadjiev¹,

Petkova²,

Chakarov³

et al. 2014

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Citation: Arabadjiev A, Petkova R, Chakarov S, Pankov R, Zhelev N. We heart cultured hearts. A comparative review of methodologies for targeted differentiation and maintenance of cardiomyocytes derived from pluripotent and multipotent stem cells. AbstractHuman cell lines, including disease cell lines are often superior to routine animal models for the purposes of rapid and safe assessment of the effects of different agents that may modulate myocardial functioning under physiological and pathological conditions. There are several currently existing methodologies for derivation of cardiomyocyte-like cells by targeted differentiation from pluripotent cells and by reprogramming/ transdifferentiation from other types of cells (multipotent progenitors, somatic cells, etc). The present paper reviews the potential sources of cells capable of differentiation along the cardiomyocyte lineage; the existing methodologies for targeted differentiation, outlining the specificities of each method; and the markers for differentiation along the mesodermal and the cardiogenic lineage. The yield of robustly beating cells expressing cardio-specific proteins derived by any of the existing methods, however, still rarely exceeds 70-90 %, even with the newly developed approaches for increasing the differentiation capacity. There still is significant variance in the results obtained by different research groups and even between different experiments carried out in the same laboratory, with the same type of cells and same general type of protocol. Derivation of new lines of human pluripotent and multipotent stem cells according to standardised protocols and in completely defined; xeno-free conditions may increase the reliability and reproducibility of research and speed up the development of potential clinical applications.

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Histone deacetylase inhibition accelerates the early events of stem cell differentiation: transcriptomic and epigenetic analysis

Cited by 94 publications

References 46 publications

Geminin promotes neural fate acquisition of embryonic stem cells by maintaining chromatin in an accessible and hyperacetylated state

Geminin promotes neural fate acquisition of embryonic stem cells by maintaining chromatin in an accessible and hyperacetylated state

Recombinant human bone morphogenetic protein-2–induced ossification of the ligamentum flavum in rats and the associated global modification of histone H3

We heart cultured hearts. A comparative review of methodologies for targeted differentiation and maintenance of cardiomyocytes derived from pluripotent and multipotent stem cells

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