scholarly journals Crotonylation promotes human embryonic stem cell endodermal lineage differentiation and metabolic switch

2021 ◽  
Author(s):  
Zhou Songyang ◽  
Jingran Zhang ◽  
Guang Shi ◽  
Junjie Pang ◽  
Xing Zhu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Large Scale ◽  
Embryonic Stem ◽  
Glycolytic Enzyme ◽  
Metabolic Switch ◽  
Post Translational Modifications ◽  
Lineage Differentiation ◽  
Metabolic Switching ◽  
Endodermal Differentiation ◽  
And Function

Abstract Post-translational modifications of proteins are crucial to the regulation of their activity and function. As a newly discovered acylation modification, crotonylation of non-histone proteins remains largely unexplored, particularly in human embryonic stem cells (hESCs). Here we report the investigation of induced crotonylation in hESCs, which resulted in hESCs of different pluripotency states differentiating into the endodermal lineage. We showed that increased protein crotonylation in hESCs was accompanied by transcriptomic shifts and decreased glycolysis. Through large-scale profiling of non-histone protein crotonylation, we identified metabolic enzymes as major targets of inducible crotonylation in hESCs. We further discovered GAPDH as a key glycolytic enzyme regulated by crotonylation during endodermal differentiation from hESCs, where crotonylation of GAPDH decreased its enzymatic activity thereby leading to reduced glycolysis. Our study demonstrates that crotonylation of glycolytic enzymes may be crucial to metabolic switching and cell fate determination in hESCs.

scholarly journals Steroidogenic Factor-1 (SF-1)-Driven Differentiation of Murine Embryonic Stem (ES) Cells into a Gonadal Lineage

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2870-2882 ◽  
Author(s):  
Unmesh Jadhav ◽  
J. Larry Jameson
Keyword(s):  
Target Genes ◽  
De Novo ◽  
Embryoid Body ◽  
Es Cells ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Culture Conditions ◽  
Steroidogenic Factor 1 ◽  
Lineage Differentiation ◽  
And Function

Steroidogenic factor 1 (SF-1) is essential for the development and function of steroidogenic tissues. Stable incorporation of SF-1 into embryonic stem cells (SF-1-ES cells) has been shown to prime the cells for steroidogenesis. When provided with exogenous cholesterol substrate, and after treatment with retinoic acid and cAMP, SF-1-ES cells produce progesterone but do not produce other steroids such as cortisol, estradiol, or testosterone. In this study, we explored culture conditions that optimize SF-1-mediated differentiation of ES cells into defined steroidogenic lineages. When embryoid body formation was used to facilitate cell lineage differentiation, SF-1-ES cells were found to be restricted in their differentiation, with fewer cells entering neuronal pathways and a larger fraction entering the steroidogenic lineage. Among the differentiation protocols tested, leukemia inhibitory factor (LIF) removal, followed by prolonged cAMP treatment was most efficacious for inducing steroidogenesis in SF-1-ES cells. In this protocol, a subset of SF-1-ES cells survives after LIF withdrawal, undergoes morphologic differentiation, and recovers proliferative capacity. These cells are characterized by induction of steroidogenic enzyme genes, use of de novo cholesterol, and production of multiple steroids including estradiol and testosterone. Microarray studies identified additional pathways associated with SF-1 mediated differentiation. Using biotinylated SF-1 in chromatin immunoprecipitation assays, SF-1 was shown to bind directly to multiple target genes, with induction of binding to some targets after steroidogenic treatment. These studies indicate that SF-1 expression, followed by LIF removal and treatment with cAMP drives ES cells into a steroidogenic pathway characteristic of gonadal steroid-producing cells.

scholarly journals iProteinDB: an integrative database of Drosophila post-translational modifications

2018 ◽  
Author(s):  
Yanhui Hu ◽  
Richelle Sopko ◽  
Verena Chung ◽  
Romain A. Studer ◽  
Sean D. Landry ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Function ◽  
Large Scale ◽  
Model Organisms ◽  
General Strategy ◽  
Post Translational Modification ◽  
Post Translational Modifications ◽  
Functional Sites ◽  
Evolutionarily Conserved ◽  
And Function

AbstractPost-translational modification (PTM) serves as a regulatory mechanism for protein function, influencing stability, protein interactions, activity and localization, and is critical in many signaling pathways. The best characterized PTM is phosphorylation, whereby a phosphate is added to an acceptor residue, commonly serine, threonine and tyrosine. As proteins are often phosphorylated at multiple sites, identifying those sites that are important for function is a challenging problem. Considering that many phosphorylation sites may be non-functional, prioritizing evolutionarily conserved phosphosites provides a general strategy to identify the putative functional sites with regards to regulation and function. To facilitate the identification of conserved phosphosites, we generated a large-scale phosphoproteomics dataset from Drosophila embryos collected from six closely-related species. We built iProteinDB (https://www.flyrnai.org/tools/iproteindb/), a resource integrating these data with other high-throughput PTM datasets, including vertebrates, and manually curated information for Drosophila. At iProteinDB, scientists can view the PTM landscape for any Drosophila protein and identify predicted functional phosphosites based on a comparative analysis of data from closely-related Drosophila species. Further, iProteinDB enables comparison of PTM data from Drosophila to that of orthologous proteins from other model organisms, including human, mouse, rat, Xenopus laevis, Danio rerio, and Caenorhabditis elegans.

Dysregulation of chromatin organization in pediatric and adult brain tumors: oncoepigenomic contributions to tumorigenesis and cancer stem cell properties

Genome ◽  
2020 ◽  
pp. 1-11
Author(s):  
Seungil Paik ◽  
Francesca Maule ◽  
Marco Gallo
Keyword(s):  
Brain Tumors ◽  
Cell Fate ◽  
Three Dimensional ◽  
Genetic Alterations ◽  
Adult Brain ◽  
Post Translational Modifications ◽  
3D Genome ◽  
Differentiated Cells ◽  
Aberrant Dna Methylation ◽  
And Function

The three-dimensional (3D) organization of the genome is a crucial enabler of cell fate, identity, and function. In this review, we will focus on the emerging role of altered 3D genome organization in the etiology of disease, with a special emphasis on brain cancers. We discuss how different genetic alterations can converge to disrupt the epigenome in childhood and adult brain tumors, by causing aberrant DNA methylation and by affecting the amounts and genomic distribution of histone post-translational modifications. We also highlight examples that illustrate how epigenomic alterations have the potential to affect 3D genome architecture in brain tumors. Finally, we will propose the concept of “epigenomic erosion” to explain the transition from stem-like cells to differentiated cells in hierarchically organized brain cancers.

scholarly journals Pancreatic Progenitor Commitment Is Marked by an Increase in Ink4a/Arf Expression

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1124
Author(s):  
Elena Montano ◽  
Alessandra Pollice ◽  
Valeria Lucci ◽  
Geppino Falco ◽  
Ornella Affinito ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Embryonic Stem ◽  
Cellular Systems ◽  
Cell Cycle Regulators ◽  
Pancreatic Progenitor ◽  
Cell Fate Decisions ◽  
Lineage Differentiation

The identification of the molecular mechanisms controlling early cell fate decisions in mammals is of paramount importance as the ability to determine specific lineage differentiation represents a significant opportunity for new therapies. Pancreatic Progenitor Cells (PPCs) constitute a regenerative reserve essential for the maintenance and regeneration of the pancreas. Besides, PPCs represent an excellent model for understanding pathological pancreatic cellular remodeling. Given the lack of valid markers of early endoderm, the identification of new ones is of fundamental importance. Both products of the Ink4a/Arf locus, in addition to being critical cell-cycle regulators, appear to be involved in several disease pathologies. Moreover, the locus’ expression is epigenetically regulated in ES reprogramming processes, thus constituting the ideal candidates to modulate PPCs homeostasis. In this study, starting from mouse embryonic stem cells (mESCs), we analyzed the early stages of pancreatic commitment. By inducing mESCs commitment to the pancreatic lineage, we observed that both products of the Cdkn2a locus, Ink4a and Arf, mark a naïve pancreatic cellular state that resembled PPC-like specification. Treatment with epi-drugs suggests a role for chromatin remodeling in the CDKN2a (Cycline Dependent Kinase Inhibitor 2A) locus regulation in line with previous observations in other cellular systems. Our data considerably improve the comprehension of pancreatic cellular ontogeny, which could be critical for implementing pluripotent stem cells programming and reprogramming toward pancreatic lineage commitment.

scholarly journals The Role of RNA Methylation in Regulating Stem Cell Fate and Function-Focus on m6A

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Weiwei Sun ◽  
Bin Zhang ◽  
Qingli Bie ◽  
Na Ma ◽  
Na Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Pluripotent Stem Cells ◽  
Adult Stem Cells ◽  
Embryonic Stem ◽  
Biological Role ◽  
Rna Methylation ◽  
Induced Pluripotent ◽  
And Function

The biological role of RNA methylation in stem cells has attracted increasing attention. Recent studies have demonstrated that RNA methylation plays a crucial role in self-renewal, differentiation, and tumorigenicity of stem cells. In this review, we focus on the biological role of RNA methylation modifications including N6-methyladenosine, 5-methylcytosine, and uridylation in embryonic stem cells, adult stem cells, induced pluripotent stem cells, and cancer stem cells, so as to provide new insights into the potential innovative treatments of cancer or other complex diseases.

scholarly journals Let-7 family of microRNA is required for maturation and adult-like metabolism in stem cell-derived cardiomyocytes

2015 ◽  
Vol 112 (21) ◽  
pp. E2785-E2794 ◽  
Author(s):  
Kavitha T. Kuppusamy ◽  
Daniel C. Jones ◽  
Henrik Sperber ◽  
Anup Madan ◽  
Karin A. Fischer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Fatty Acid ◽  
Large Scale ◽  
Metabolic Flux ◽  
Embryonic Stem ◽  
Acid Oxidation ◽  
Loss Of Function ◽  
Metabolic Switch ◽  
Cardiac Maturation

In metazoans, transition from fetal to adult heart is accompanied by a switch in energy metabolism-glycolysis to fatty acid oxidation. The molecular factors regulating this metabolic switch remain largely unexplored. We first demonstrate that the molecular signatures in 1-year (y) matured human embryonic stem cell-derived cardiomyocytes (hESC-CMs) are similar to those seen in in vivo-derived mature cardiac tissues, thus making them an excellent model to study human cardiac maturation. We further show that let-7 is the most highly up-regulated microRNA (miRNA) family during in vitro human cardiac maturation. Gain- and loss-of-function analyses of let-7g in hESC-CMs demonstrate it is both required and sufficient for maturation, but not for early differentiation of CMs. Overexpression of let-7 family members in hESC-CMs enhances cell size, sarcomere length, force of contraction, and respiratory capacity. Interestingly, large-scale expression data, target analysis, and metabolic flux assays suggest this let-7–driven CM maturation could be a result of down-regulation of the phosphoinositide 3 kinase (PI3K)/AKT protein kinase/insulin pathway and an up-regulation of fatty acid metabolism. These results indicate let-7 is an important mediator in augmenting metabolic energetics in maturing CMs. Promoting maturation of hESC-CMs with let-7 overexpression will be highly significant for basic and applied research.

scholarly journals MicroRNA Expression Patterns and Function in Endodermal Differentiation of Human Embryonic Stem Cells

PLoS ONE ◽  
2008 ◽  
Vol 3 (11) ◽  
pp. e3726 ◽  
Author(s):  
Galit Tzur ◽  
Asaf Levy ◽  
Eti Meiri ◽  
Omer Barad ◽  
Yael Spector ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Expression Patterns ◽  
Embryonic Stem ◽  
Microrna Expression ◽  
Endodermal Differentiation ◽  
And Function

scholarly journals Intra-individual methylomics detects the impact of early-life adversity

2018 ◽  
Author(s):  
Shan Jiang ◽  
Noriko Kamei ◽  
Jessica L. Bolton ◽  
Xinyi Ma ◽  
Hal S. Stern ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Fate ◽  
Early Life ◽  
Large Scale ◽  
Life Experience ◽  
Early Life Adversity ◽  
Health And Disease ◽  
Genetic And Environmental Factors ◽  
And Function ◽  
The Impact

AbstractGenetic and environmental factors interact during sensitive periods early in life to influence mental health and disease via epigenetic processes such as DNA methylation. However, it is not known if DNA methylation changes outside the brain provide an ‘epigenetic signature’ of early-life experiences. Here, we employed a novel intra-individual approach by testing DNA methylation from buccal cells of individual rats before and immediately after exposure to one week of typical or adverse life experience. We find that whereas inter-individual changes in DNA methylation reflect the effect of age, DNA methylation changes within paired DNA samples from the same individual reflect the impact of diverse neonatal experiences. Genes coding for critical cellular–metabolic enzymes, ion channels and receptors were more methylated in pups exposed to the adverse environment, predictive of their repression. In contrast, the adverse experience was associated with less methylation on genes involved in pathways of death and inflammation as well as cell-fate related transcription factors, indicating their potential upregulation. Thus, intra-individual methylome signatures indicate large-scale transcription-driven alterations of cellular fate, growth and function.

scholarly journals Intra-individual methylomics detects the impact of early-life adversity

2019 ◽  
Vol 2 (2) ◽  
pp. e201800204 ◽  
Author(s):  
Shan Jiang ◽  
Noriko Kamei ◽  
Jessica L Bolton ◽  
Xinyi Ma ◽  
Hal S Stern ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cell Fate ◽  
Early Life ◽  
Large Scale ◽  
Life Experience ◽  
Early Life Adversity ◽  
Health And Disease ◽  
Genetic And Environmental Factors ◽  
And Function ◽  
The Impact

Genetic and environmental factors interact during sensitive periods early in life to influence mental health and disease via epigenetic processes such as DNA methylation. However, it is not known if DNA methylation changes outside the brain provide an “epigenetic signature” of early-life experiences. Here, we used a novel intra-individual approach by testing DNA methylation from buccal cells of individual rats before and immediately after exposure to one week of typical or adverse life experience. We find that whereas inter-individual changes in DNA methylation reflect the effect of age, DNA methylation changes within paired DNA samples from the same individual reflect the impact of diverse neonatal experiences. Genes coding for critical cellular metabolic enzymes, ion channels, and receptors were more methylated in pups exposed to the adverse environment, predictive of their repression. In contrast, the adverse experience was associated with less methylation on genes involved in pathways of death and inflammation as well as cell-fate–related transcription factors, indicating their potential up-regulation. Thus, intra-individual methylome signatures indicate large-scale transcription-driven alterations of cellular fate, growth, and function.

scholarly journals Mapping the route from naive pluripotency to lineage specification

2014 ◽  
Vol 369 (1657) ◽  
pp. 20130540 ◽  
Author(s):  
Tüzer Kalkan ◽  
Austin Smith
Keyword(s):  
Stem Cells ◽  
Large Scale ◽  
Developmental Plasticity ◽  
Embryonic Stem ◽  
State Transitions ◽  
Mouse Blastocyst ◽  
Lineage Specification ◽  
Road Map ◽  
Lineage Differentiation

In the mouse blastocyst, epiblast cells are newly formed shortly before implantation. They possess a unique developmental plasticity, termed naive pluripotency. For development to proceed, this naive state must be subsumed by multi-lineage differentiation within 72 h following implantation. In vitro differentiation of naive embryonic stem cells (ESCs) cultured in controlled conditions provides a tractable system to dissect and understand the process of exit from naive pluripotency and entry into lineage specification. Exploitation of this system in recent large-scale RNAi and mutagenesis screens has uncovered multiple new factors and modules that drive or facilitate progression out of the naive state. Notably, these studies show that the transcription factor network that governs the naive state is rapidly dismantled prior to upregulation of lineage specification markers, creating an intermediate state that we term formative pluripotency. Here, we summarize these findings and propose a road map for state transitions in ESC differentiation that reflects the orderly dynamics of epiblast progression in the embryo.

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