scholarly journals INO80 promotes H2A.Z occupancy to regulate cell fate transition in pluripotent stem cells

2020 ◽  
Author(s):  
Hongyao Yu ◽  
Jiajia Wang ◽  
Brad Lackford ◽  
Brian Bennett ◽  
Jian-liang Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Control Cell ◽  
Epigenetic Mechanism ◽  
Gene Repression ◽  
Gene Promoters ◽  
Cellular Functions ◽  
The Impact

AbstractThe INO80 chromatin remodeler is involved in many chromatin-dependent cellular functions. However, its role in pluripotency and cell fate transition is not fully defined. We examined the impact of Ino80 deletion in the naïve and primed pluripotent stem cells. We found that Ino80 deletion had minimal effect on self-renewal and gene expression in the naïve state, but led to cellular differentiation and de-repression of developmental genes in the transition toward and maintenance of the primed state. Mechanistically, INO80 pre-marked gene promoters that would adopt the H3K4me3 and H3K27me3 bivalent histone modifications. It promoted H2A.Z occupancy at these future bivalent domains to facilitate H3K27me3 installation and maintenance as well as downstream gene repression. Thus, INO80-dependent H2A.Z occupancy is a critical a licensing step for bivalency and poised gene expression in pluripotent stem cells. Our results uncovered an unexpected function of INO80 in H2A.Z deposition and gene repression, and an epigenetic mechanism by which chromatin remodeling, histone variant and modification coordinately control cell fate.

scholarly journals AMPKβ1 and AMPKβ2 define an isoform-specific gene signature in human pluripotent stem cells, differentially mediating cardiac lineage specification

2020 ◽  
Vol 295 (51) ◽  
pp. 17659-17671
Author(s):  
Nicole Ziegler ◽  
Erik Bader ◽  
Alexey Epanchintsev ◽  
Daniel Margerie ◽  
Aimo Kannt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Specific Gene ◽  
Wide Range ◽  
Specific Manner ◽  
Cardiac Lineage

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism that phosphorylates a wide range of proteins to maintain cellular homeostasis. AMPK consists of three subunits: α, β, and γ. AMPKα and β are encoded by two genes, the γ subunit by three genes, all of which are expressed in a tissue-specific manner. It is not fully understood, whether individual isoforms have different functions. Using RNA-Seq technology, we provide evidence that the loss of AMPKβ1 and AMPKβ2 lead to different gene expression profiles in human induced pluripotent stem cells (hiPSCs), indicating isoform-specific function. The knockout of AMPKβ2 was associated with a higher number of differentially regulated genes than the deletion of AMPKβ1, suggesting that AMPKβ2 has a more comprehensive impact on the transcriptome. Bioinformatics analysis identified cell differentiation as one biological function being specifically associated with AMPKβ2. Correspondingly, the two isoforms differentially affected lineage decision toward a cardiac cell fate. Although the lack of PRKAB1 impacted differentiation into cardiomyocytes only at late stages of cardiac maturation, the availability of PRKAB2 was indispensable for mesoderm specification as shown by gene expression analysis and histochemical staining for cardiac lineage markers such as cTnT, GATA4, and NKX2.5. Ultimately, the lack of AMPKβ1 impairs, whereas deficiency of AMPKβ2 abrogates differentiation into cardiomyocytes. Finally, we demonstrate that AMPK affects cellular physiology by engaging in the regulation of hiPSC transcription in an isoform-specific manner, providing the basis for further investigations elucidating the role of dedicated AMPK subunits in the modulation of gene expression.

scholarly journals Transcription factors orchestrate dynamic interplay between genome topology and gene regulation during cell reprogramming

2017 ◽  
Author(s):  
Ralph Stadhouders ◽  
Enrique Vidal ◽  
François Serra ◽  
Bruno Di Stefano ◽  
François Le Dily ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Transcription Factors ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Time Resolved ◽  
Genome Reorganization ◽  
Chromosomal Architecture ◽  
Dynamic Interplay ◽  
Pluripotency Genes

ABSTRACTChromosomal architecture is known to influence gene expression, yet its role in controlling cell fate remains poorly understood. Reprogramming of somatic cells into pluripotent stem cells by the transcription factors (TFs) Oct4, Sox2, Klf4 and Myc offers an opportunity to address this question but is severely limited by the low proportion of responding cells. We recently developed a highly efficient reprogramming protocol that synchronously converts somatic into pluripotent stem cells. Here, we employ this system to integrate time-resolved changes in genome topology with gene expression, TF binding and chromatin state dynamics. This revealed that TFs drive topological genome reorganization at multiple architectural levels, which often precedes changes in gene expression. Removal of locus-specific topological barriers can explain why pluripotency genes are activated sequentially, instead of simultaneously, during reprogramming. Taken together, our study implicates genome topology as an instructive force for implementing transcriptional programs and cell fate in mammals.

scholarly journals Potential Threats of Nanoplastic Accumulation in Human Induced Pluripotent Stem Cells

2021 ◽  
Author(s):  
Hyejoong Jeong ◽  
Wijin Kim ◽  
Daheui Choi ◽  
Jiwoong Heo ◽  
Uiyoung Han ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Cellular Functions ◽  
Differentiation Potential ◽  
Developmental Toxicology ◽  
Neural Lineage ◽  
Induced Pluripotent ◽  
The Impact

Abstract Background: Micro- and nanoplastics (NPs) produced from the bulk fragmentation are rampant in the world by enormous plastic trash everyday life. NPs can be exposed to humans through a variety of routes, including inhalation and intake. The threat to humans from NPs is increasing invisibly. Nowadays, many people are concerned about human safety and health, but few are reported about the effects of NP on humans. To overcome the limitations in human studies, human induced pluripotent stem cells (hiPSCs) were used as an optimal in vitro platform to investigate developmental toxicology and subtle changes on cellular functions in terms of differentiation potential throughout a long-term culture. Results: Negatively charged polystyrene nanoplastics (PS NPs) were used to exclude acute toxic issues of surface charge and investigate the impact of the NP's size and nature during bioaccumulation. Intracellular observations revealed that NPs up to 1000 nm were over-internalized into single cells within 48 h, and smaller NPs demonstrated greater potency at decreasing number of viable cells by a strong correlation with the number of NPs on an equal mass basis. Also, PS NPs caused a significant reduction in self-renewal capacity of hiPSCs for 48 h. After the cells were exposed to PS NPs for 48 to 96 h at the beginning of the differentiation process, NPs accumulated in hiPSC did not render cellular functions vulnerable or adversely affect EB formation, EB-mediated differentiation, and neural lineage differentiation for up to 14 days.Conclusion: This study confirmed that hiPSC exposure to polystyrene nanoplastics results in acute toxicity and non-significant long-term effects on cellular functions. This report is important for understanding the developmental toxicology of nanoplastics and the origin of disease.

scholarly journals Mitochondrial Heterogeneity: Evaluating Mitochondrial Subpopulation Dynamics in Stem Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
D. C. Woods
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Cell Biology ◽  
Cell Types ◽  
Cellular Reprogramming ◽  
Cellular Functions ◽  
Technical Advances ◽  
Mitochondrial Heterogeneity ◽  
Key Participants

Although traditionally viewed as the “powerhouse” of the cell, an accruing body of evidence in the rapidly growing field of mitochondrial biology supports additional roles of mitochondria as key participants in a multitude of cellular functions. While it has been well established that mitochondria in different tissues have distinctive ultrastructural features consistent with differential bioenergetic demands, recent and emerging technical advances in flow cytometry, imaging, and “-omics”-based bioinformatics have only just begun to explore the complex and divergent properties of mitochondria within tissues and cell types. Moreover, contemporary studies evaluating the role of mitochondria in pluripotent stem cells, cellular reprogramming, and differentiation point to a potential importance of mitochondrial subpopulations and heterogeneity in the field of stem cell biology. This review assesses the current literature regarding mitochondrial subpopulations within cell and tissue types and evaluates the current understanding of how mitochondrial diversity and heterogeneity might impact cell fate specification in pluripotent stem cells.

scholarly journals Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition

2016 ◽  
Vol 113 (42) ◽  
pp. 11871-11876 ◽  
Author(s):  
Chaochen Wang ◽  
Ji-Eun Lee ◽  
Binbin Lai ◽  
Todd S. Macfarlan ◽  
Shiliyang Xu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Cell Fate ◽  
Control Cell ◽  
Embryonic Stem ◽  
Specific Gene ◽  
Cell Identity ◽  
Identity Maintenance ◽  
Cell Type Specific ◽  
Induced Pluripotent

Transcriptional enhancers control cell-type–specific gene expression. Primed enhancers are marked by histone H3 lysine 4 (H3K4) mono/di-methylation (H3K4me1/2). Active enhancers are further marked by H3K27 acetylation (H3K27ac). Mixed-lineage leukemia 4 (MLL4/KMT2D) is a major enhancer H3K4me1/2 methyltransferase with functional redundancy with MLL3 (KMT2C). However, its role in cell fate maintenance and transition is poorly understood. Here, we show in mouse embryonic stem cells (ESCs) that MLL4 associates with, but is surprisingly dispensable for the maintenance of, active enhancers of cell-identity genes. As a result, MLL4 is dispensable for cell-identity gene expression and self-renewal in ESCs. In contrast, MLL4 is required for enhancer-binding of H3K27 acetyltransferase p300, enhancer activation, and induction of cell-identity genes during ESC differentiation. MLL4 protein, rather than MLL4-mediated H3K4 methylation, controls p300 recruitment to enhancers. We also show that, in somatic cells, MLL4 is dispensable for maintaining cell identity but essential for reprogramming into induced pluripotent stem cells. These results indicate that, although enhancer priming by MLL4 is dispensable for cell-identity maintenance, it controls cell fate transition by orchestrating p300-mediated enhancer activation.

scholarly journals Modulation of Human Mesenchymal Stem Cells by Electrical Stimulation Using an Enzymatic Biofuel Cell

Catalysts ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 62
Author(s):  
Won-Yong Jeon ◽  
Seyoung Mun ◽  
Wei Beng Ng ◽  
Keunsoo Kang ◽  
Kyudong Han ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Electrical Stimulation ◽  
Regenerative Medicine ◽  
Cell Morphology ◽  
Electrical Current ◽  
Specific Gene ◽  
Next Generation ◽  
The Impact

Enzymatic biofuel cells (EBFCs) have excellent potential as components in bioelectronic devices, especially as active biointerfaces to regulate stem cell behavior for regenerative medicine applications. However, it remains unclear to what extent EBFC-generated electrical stimulation can regulate the functional behavior of human adipose-derived mesenchymal stem cells (hAD-MSCs) at the morphological and gene expression levels. Herein, we investigated the effect of EBFC-generated electrical stimulation on hAD-MSC cell morphology and gene expression using next-generation RNA sequencing. We tested three different electrical currents, 127 ± 9, 248 ± 15, and 598 ± 75 nA/cm2, in mesenchymal stem cells. We performed transcriptome profiling to analyze the impact of EBFC-derived electrical current on gene expression using next generation sequencing (NGS). We also observed changes in cytoskeleton arrangement and analyzed gene expression that depends on the electrical stimulation. The electrical stimulation of EBFC changes cell morphology through cytoskeleton re-arrangement. In particular, the results of whole transcriptome NGS showed that specific gene clusters were up- or down-regulated depending on the magnitude of applied electrical current of EBFC. In conclusion, this study demonstrates that EBFC-generated electrical stimulation can influence the morphological and gene expression properties of stem cells; such capabilities can be useful for regenerative medicine applications such as bioelectronic devices.

scholarly journals T9. EPIGENETIC PROFILING IN SCHIZOPHRENIA DERIVED HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS) AND NEURONS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S234-S234
Author(s):  
Lorna Farrelly ◽  
Shuangping Zhang ◽  
Erin Flaherty ◽  
Aaron Topol ◽  
Nadine Schrode ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mass Spectrometry ◽  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Neural Progenitor Cells ◽  
Gene Expression Pattern ◽  
Early Gene ◽  
Label Free ◽  
Induced Pluripotent

Abstract Background Schizophrenia (SCZ) is a severe psychiatric disorder affecting ~1% of the world’s population. It is largely heritable with genetic risk reflected by a combination of common variants of small effect and highly penetrant rare mutations. Chromatin modifications are known to play critical roles in the mediation of many neurodevelopmental processes, and, when disturbed, may also contribute to the precipitation of psychiatric disorders, such as SCZ. While a handful of candidate-based studies have measured changes in promoter-bound histone modifications, few mechanistic studies have been carried out to explore how these modifications may affect chromatin to precipitate behavioral phenotypes associated with the disease. Methods We applied an unbiased proteomics approach to evaluate the epigenetic landscape of SCZ in human induced pluripotent stem cells (hiPSC), neural progenitor cells (NPCs) and neurons from SCZ patients vs. matched controls. We utilized proteomics-based, label free liquid chromatography mass spectrometry (LC-MS/MS) on purified histones from these cells and confirmed our results by western blotting in postmortem SCZ cortical brain tissues. Furthermore we validated our findings with the application of histone interaction assays and structural and biophysical assessments to identify and confirm novel chromatin ‘readers’. To relate our findings to a SCZ phenotype we used a SCZ rodent model of prepulse inhibition (PPI) to perform pharmacological manipulations and behavioral assessments. Results Using label free mass spectrometry we performed PTM screening of hiPSCs, NPCs and matured neurons derived from SCZ patients and matched controls. We identified, amongst others, altered patterns of hyperacetylation in SCZ neurons. Additionally we identified enhanced binding of particular acetylation ‘reader’ proteins. Pharmacological inhibition of such proteins in an animal model of amphetamine sensitization ameliorated PPI deficits further validating this epigenetic signature in SCZ. Discussion Recent evidence indicates that relevance and patterns of acetylation in epigenetics advances beyond its role in transcription and small molecule inhibitors of these aberrant interactions hold promise as useful therapeutics. This study identifies a role for modulating gene expression changes associated with a SCZ epigenetic signature and warrants further investigation in terms of how this early gene expression pattern perhaps determines susceptibility or severity of the SCZ disease trajectory.

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