Quantifying the Stability of Coupled Genetic and Epigenetic Switches With Variational Methods

The Waddington landscape provides an intuitive metaphor to view development as a ball rolling down the hill, with distinct phenotypes as basins and differentiation pathways as valleys. Since, at a molecular level, cell differentiation arises from interactions among the genes, a mathematical definition for the Waddington landscape can, in principle, be obtained by studying the gene regulatory networks. For eukaryotes, gene regulation is inextricably and intimately linked to histone modifications. However, the impact of such modifications on both landscape topography and stability of attractor states is not fully understood. In this work, we introduced a minimal kinetic model for gene regulation that combines the impact of both histone modifications and transcription factors. We further developed an approximation scheme based on variational principles to solve the corresponding master equation in a second quantized framework. By analyzing the steady-state solutions at various parameter regimes, we found that histone modification kinetics can significantly alter the behavior of a genetic network, resulting in qualitative changes in gene expression profiles. The emerging epigenetic landscape captures the delicate interplay between transcription factors and histone modifications in driving cell-fate decisions.

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The Impact of Epigenetic Signatures on Amniotic Fluid Stem Cell Fate

Stem Cells International ◽

10.1155/2018/4274518 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Daniela Di Tizio ◽

Alessandra Di Serafino ◽

Prabin Upadhyaya ◽

Luca Sorino ◽

Liborio Stuppia ◽

...

Keyword(s):

Dna Methylation ◽

Stem Cells ◽

Amniotic Fluid ◽

Cell Fate ◽

Histone Modifications ◽

Current Evidence ◽

Cell Fate Decisions ◽

Small Noncoding Rnas ◽

Tight Correlation ◽

The Impact

Epigenetic modifications play a significant role in determining the fate of stem cells and in directing the differentiation into multiple lineages. Current evidence indicates that mechanisms involved in chromatin regulation are essential for maintaining stable cell identities. There is a tight correlation among DNA methylation, histone modifications, and small noncoding RNAs during the epigenetic control of stem cells’ differentiation; however, to date, the precise mechanism is still not clear. In this context, amniotic fluid stem cells (AFSCs) represent an interesting model due to their unique features and the possible advantages of their use in regenerative medicine. Recent studies have elucidated epigenetic profiles involved in AFSCs’ lineage commitment and differentiation. In order to use these cells effectively for therapeutic purposes, it is necessary to understand the basis of multiple-lineage potential and elaborate in detail how cell fate decisions are made and memorized. The present review summarizes the most recent findings on epigenetic mechanisms of AFSCs with a focus on DNA methylation, histone modifications, and microRNAs (miRNAs) and addresses how their unique signatures contribute to lineage-specific differentiation.

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Expression Profiles of MicroRNAs in Stem Cells Differentiation

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666200219092520 ◽

2020 ◽

Vol 21 (10) ◽

pp. 906-918

Author(s):

Hadi Rajabi ◽

Somayeh Aslani ◽

Alireza Abhari ◽

Davoud Sanajou

Keyword(s):

Stem Cells ◽

Transcription Factors ◽

Signaling Pathways ◽

Cell Fate ◽

Adult Stem Cells ◽

Expression Profiles ◽

Embryonic Stem ◽

Stem Cell Differentiation ◽

Cell Fate Decisions ◽

Effective Diagnosis

Stem cells are undifferentiated cells and have a great potential in multilineage differentiation. These cells are classified into adult stem cells like Mesenchymal Stem Cells (MSCs) and Embryonic Stem Cells (ESCs). Stem cells also have potential therapeutic utility due to their pluripotency, self-renewal, and differentiation ability. These properties make them a suitable choice for regenerative medicine. Stem cells differentiation toward functional cells is governed by different signaling pathways and transcription factors. Recent studies have demonstrated the key role of microRNAs in the pathogenesis of various diseases, cell cycle regulation, apoptosis, aging, cell fate decisions. Several types of stem cells have different and unique miRNA expression profiles. Our review summarizes novel regulatory roles of miRNAs in the process of stem cell differentiation especially adult stem cells into a variety of functional cells through signaling pathways and transcription factors modulation. Understanding the mechanistic roles of miRNAs might be helpful in elaborating clinical therapies using stem cells and developing novel biomarkers for the early and effective diagnosis of pathologic conditions.

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A Gene Regulatory Network Controlled by BpERF2 and BpMYB102 in Birch under Drought Conditions

International Journal of Molecular Sciences ◽

10.3390/ijms20123071 ◽

2019 ◽

Vol 20 (12) ◽

pp. 3071 ◽

Cited By ~ 6

Author(s):

Xuejing Wen ◽

Jingxin Wang ◽

Daoyuan Zhang ◽

Yucheng Wang

Keyword(s):

Transcription Factors ◽

Drought Tolerance ◽

Regulatory Networks ◽

Expression Profiles ◽

Plant Stress ◽

Gene Expression Profiles ◽

Water Shortage ◽

Late Embryogenesis Abundant ◽

Ros Scavenging ◽

Pathogenesis Related Protein

Gene expression profiles are powerful tools for investigating mechanisms of plant stress tolerance. Betula platyphylla (birch) is a widely distributed tree, but its drought-tolerance mechanism has been little studied. Using RNA-Seq, we identified 2917 birch genes involved in its response to drought stress. These drought-responsive genes include the late embryogenesis abundant (LEA) family, heat shock protein (HSP) family, water shortage-related and ROS-scavenging proteins, and many transcription factors (TFs). Among the drought-induced TFs, the ethylene responsive factor (ERF) and myeloblastosis oncogene (MYB) families were the most abundant. BpERF2 and BpMYB102, which were strongly induced by drought and had high transcription levels, were selected to study their regulatory networks. BpERF2 and BpMYB102 both played roles in enhancing drought tolerance in birch. Chromatin immunoprecipitation combined with qRT-PCR indicated that BpERF2 regulated genes such as those in the LEA and HSP families, while BpMYB102 regulated genes such as Pathogenesis-related Protein 1 (PRP1) and 4-Coumarate:Coenzyme A Ligase 10 (4CL10). Multiple genes were regulated by both BpERF2 and BpMYB102. We further characterized the function of some of these genes, and the genes that encode Root Primordium Defective 1 (RPD1), PRP1, 4CL10, LEA1, SOD5, and HSPs were found to be involved in drought tolerance. Therefore, our results suggest that BpERF2 and BpMYB102 serve as transcription factors that regulate a series of drought-tolerance genes in B. platyphylla to improve drought tolerance.

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Comparative transcriptome analysis of Trichoderma reesei reveals different gene regulatory networks induced by synthetic mixtures of glucose and β-disaccharide

Bioresources and Bioprocessing ◽

10.1186/s40643-021-00411-4 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Yonghao Li ◽

Jingze Yu ◽

Peng Zhang ◽

Tingting Long ◽

Yi Mo ◽

...

Keyword(s):

Transcription Factors ◽

Trichoderma Reesei ◽

Regulatory Networks ◽

Expression Profiles ◽

Low Cost ◽

Strain Improvement ◽

Gene Expression Profiles ◽

Cellulase Production ◽

Mitogen Activated Protein Kinase ◽

Lignocellulose Degradation

AbstractThe mixture of glucose and β-disaccharide (MGD) synthesized by transglycosylation of glucose as a low-cost soluble carbon source can efficiently induce cellulase production in Trichoderma reesei, which holds potential for the biorefining of lignocellulosic biomass. However, it is not yet fully understood how MGD induces T. reesei cellulase. In this study, transcriptomic analyses were conducted to investigate the molecular basis of MGD for lignocellulose-degrading enzyme production of T. reesei Rut C30 compared with that on lactose. Particular attention was paid to CAZymes, transcription factors, transporters and other protein processing pathways related to lignocellulose degradation. As a result, MGD can elicit transcription of GH5-, GH6- and GH7-encoding cellulases that is up to 1.4-fold higher than that induced by lactose, but GH11- and GH74-encoding xylanases are downregulated by 1.7- and 4.4-fold, respectively. Gene expression profiles suggest that the transcription activators xyr1 and vib1 are significantly upregulated and that the mitogen-activated protein kinase pathway is strengthened compared to the case of lactose induction. In addition, hac1-encoding UPR-specific transcription factors are significantly upregulated by MGD, which may be enhanced due to proper folding and processing of nascent proteins. These findings provide a theoretical basis for further understanding the characterization of efficient cellulase production using MGD as an inducer in T. reesei and offer potential strategies for strain improvement.

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Long Non-Coding RNAs in the Control of Gametogenesis: Lessons from Fission Yeast

Non-Coding RNA ◽

10.3390/ncrna7020034 ◽

2021 ◽

Vol 7 (2) ◽

pp. 34

Author(s):

Vedrana Andric ◽

Mathieu Rougemaille

Keyword(s):

Fission Yeast ◽

Cell Fate ◽

Genetic Information ◽

Developmental Process ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cell Fate Decisions ◽

Genome Expression ◽

Non Coding Rnas ◽

Cycle Dependent

Long non-coding RNAs (lncRNAs) contribute to cell fate decisions by modulating genome expression and stability. In the fission yeast Schizosaccharomyces pombe, the transition from mitosis to meiosis results in a marked remodeling of gene expression profiles, which ultimately ensures gamete production and inheritance of genetic information to the offspring. This key developmental process involves a set of dedicated lncRNAs that shape cell cycle-dependent transcriptomes through a variety of mechanisms, including epigenetic modifications and the modulation of transcription, post-transcriptional and post-translational regulations, and that contribute to meiosis-specific chromosomal events. In this review, we summarize the biology of these lncRNAs, from their identification to mechanism of action, and discuss their regulatory role in the control of gametogenesis.

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Influence of Nanotopography on Early Bone Healing during Controlled Implant Loading

Nanomaterials ◽

10.3390/nano10112191 ◽

2020 ◽

Vol 10 (11) ◽

pp. 2191

Author(s):

Renan de Barros e Lima Bueno ◽

Katia Ponce ◽

Ana Dias ◽

Dainelys Guadarrama Bello ◽

John Brunski ◽

...

Keyword(s):

Bone Formation ◽

Cell Fate ◽

Bone Healing ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Implant Surface ◽

Bone Implant ◽

Cell Fate Decisions ◽

High Bone ◽

Implant Loading

Nanoscale surface modifications influence peri-implant cell fate decisions and implant loading generates local tissue deformation, both of which will invariably impact bone healing. The objective of this study is to determine how loading affects healing around implants with nanotopography. Implants with a nanoporous surface were placed in over-sized osteotomies in rat tibiae and held stable by a system that permits controlled loading. Three regimens were applied: (a) no loading, (b) one daily loading session with a force of 1.5N, and (c) two such daily sessions. At 7 days post implantation, animals were sacrificed for histomorphometric and DNA microarray analyses. Implants subjected to no loading or only one daily loading session achieved high bone-implant contact (BIC), bone-implant distance (BID) and bone formation area near the implant (BFAt) values, while those subjected to two daily loading sessions showed less BFAt and BIC and more BID. Gene expression profiles differed between all groups mainly in unidentified genes, and no modulation of genes associated with inflammatory pathways was detected. These results indicate that implants with nanotopography can achieve a high level of bone formation even under micromotion and limit the inflammatory response to the implant surface.

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Pluripotency Factors on Their Lineage Move

Stem Cells International ◽

10.1155/2016/6838253 ◽

2016 ◽

Vol 2016 ◽

pp. 1-16 ◽

Cited By ~ 6

Author(s):

Clair E. Weidgang ◽

Thomas Seufferlein ◽

Alexander Kleger ◽

Martin Mueller

Keyword(s):

Transcription Factors ◽

Cell Fate ◽

Ground State ◽

Regulatory Networks ◽

Embryonic Stem ◽

Lineage Specification ◽

Developmental Potential ◽

Cell Fate Decisions ◽

Complex Interactions ◽

Great Knowledge

Pluripotent stem cells are characterised by continuous self-renewal while maintaining the potential to differentiate into cells of all three germ layers. Regulatory networks of maintaining pluripotency have been described in great detail and, similarly, there is great knowledge on key players that regulate their differentiation. Interestingly, pluripotency has various shades with distinct developmental potential, an observation that coined the term of a ground state of pluripotency. A precise interplay of signalling axes regulates ground state conditions and acts in concert with a combination of key transcription factors. The balance between these transcription factors greatly influences the integrity of the pluripotency network and latest research suggests that minute changes in their expression can strengthen but also collapse the network. Moreover, recent studies reveal different facets of these core factors in balancing a controlled and directed exit from pluripotency. Thereby, subsets of pluripotency-maintaining factors have been shown to adopt new roles during lineage specification and have been globally defined towards neuroectodermal and mesendodermal sets of embryonic stem cell genes. However, detailed underlying insights into how these transcription factors orchestrate cell fate decisions remain largely elusive. Our group and others unravelled complex interactions in the regulation of this controlled exit. Herein, we summarise recent findings and discuss the potential mechanisms involved.

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Controlling gene networks and cell fate with precision-targeted DNA-binding proteins and small-molecule-based genome readers

Biochemical Journal ◽

10.1042/bj20140400 ◽

2014 ◽

Vol 462 (3) ◽

pp. 397-413 ◽

Cited By ~ 10

Author(s):

Asuka Eguchi ◽

Garrett O. Lee ◽

Fang Wan ◽

Graham S. Erwin ◽

Aseem Z. Ansari

Keyword(s):

Transcription Factors ◽

Dna Binding ◽

Cell Fate ◽

Gene Networks ◽

Regulatory Networks ◽

Transcriptional Networks ◽

Cell Fate Decisions ◽

Differentiated Cells ◽

Dna Binding Factors ◽

Dna Binders

Transcription factors control the fate of a cell by regulating the expression of genes and regulatory networks. Recent successes in inducing pluripotency in terminally differentiated cells as well as directing differentiation with natural transcription factors has lent credence to the efforts that aim to direct cell fate with rationally designed transcription factors. Because DNA-binding factors are modular in design, they can be engineered to target specific genomic sequences and perform pre-programmed regulatory functions upon binding. Such precision-tailored factors can serve as molecular tools to reprogramme or differentiate cells in a targeted manner. Using different types of engineered DNA binders, both regulatory transcriptional controls of gene networks, as well as permanent alteration of genomic content, can be implemented to study cell fate decisions. In the present review, we describe the current state of the art in artificial transcription factor design and the exciting prospect of employing artificial DNA-binding factors to manipulate the transcriptional networks as well as epigenetic landscapes that govern cell fate.

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GATA-targeted compounds modulate cardiac subtype cell differentiation in dual reporter stem cell line

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02259-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Mika J. Välimäki ◽

Robert S. Leigh ◽

Sini M. Kinnunen ◽

Alexander R. March ◽

Ana Hernández de Sande ◽

...

Keyword(s):

Gene Expression ◽

Progenitor Cells ◽

Cell Fate ◽

Reporter Gene ◽

Gene Regulatory Networks ◽

Regulatory Networks ◽

Cell Fate Decisions ◽

Dual Reporter ◽

Gene Regulatory ◽

Reporter Gene Assays

AbstractBackgroundPharmacological modulation of cell fate decisions and developmental gene regulatory networks holds promise for the treatment of heart failure. Compounds that target tissue-specific transcription factors could overcome non-specific effects of small molecules and lead to the regeneration of heart muscle following myocardial infarction. Due to cellular heterogeneity in the heart, the activation of gene programs representing specific atrial and ventricular cardiomyocyte subtypes would be highly desirable. Chemical compounds that modulate atrial and ventricular cell fate could be used to improve subtype-specific differentiation of endogenous or exogenously delivered progenitor cells in order to promote cardiac regeneration.MethodsTranscription factor GATA4-targeted compounds that have previously shown in vivo efficacy in cardiac injury models were tested for stage-specific activation of atrial and ventricular reporter genes in differentiating pluripotent stem cells using a dual reporter assay. Chemically induced gene expression changes were characterized by qRT-PCR, global run-on sequencing (GRO-seq) and immunoblotting, and the network of cooperative proteins of GATA4 and NKX2-5 were further explored by the examination of the GATA4 and NKX2-5 interactome by BioID. Reporter gene assays were conducted to examine combinatorial effects of GATA-targeted compounds and bromodomain and extraterminal domain (BET) inhibition on chamber-specific gene expression.ResultsGATA4-targeted compounds 3i-1000 and 3i-1103 were identified as differential modulators of atrial and ventricular gene expression. More detailed structure-function analysis revealed a distinct subclass of GATA4/NKX2-5 inhibitory compounds with an acetyl lysine-like domain that contributed to ventricular cells (%Myl2-eGFP+). Additionally, BioID analysis indicated broad interaction between GATA4 and BET family of proteins, such as BRD4. This indicated the involvement of epigenetic modulators in the regulation of GATA-dependent transcription. In this line, reporter gene assays with combinatorial treatment of 3i-1000 and the BET bromodomain inhibitor (+)-JQ1 demonstrated the cooperative role of GATA4 and BRD4 in the modulation of chamber-specific cardiac gene expression.ConclusionsCollectively, these results indicate the potential for therapeutic alteration of cell fate decisions and pathological gene regulatory networks by GATA4-targeted compounds modulating chamber-specific transcriptional programs in multipotent cardiac progenitor cells and cardiomyocytes. The compound scaffolds described within this study could be used to develop regenerative strategies for myocardial regeneration.

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Integrated Genomic Analysis of Sézary Syndrome

Genetics Research International ◽

10.4061/2011/980150 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Xin Mao ◽

Tracy Chaplin ◽

Bryan D. Young

Keyword(s):

Copy Number ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Genomic Analysis ◽

Gene Clusters ◽

Sézary Syndrome ◽

Sezary Syndrome ◽

Snp Microarray ◽

The Impact ◽

Chromosome Regions

Sézary syndrome (SS) is a rare variant of primary cutaneous T-cell lymphoma. Little is known about the underlying pathogenesis of S. To address this issue, we used Affymetrix 10K SNP microarray to analyse 13 DNA samples isolated from 8 SS patients and qPCR with ABI TaqMan SNP genotyping assays for the validation of the SNP microarray results. In addition, we tested the impact of SNP loss of heterozygosity (LOH) identified in SS cases on the gene expression profiles of SS cases detected with Affymetrix GeneChip U133A. The results showed: (1) frequent SNP copy number change and LOH involving 1, 2p, 3, 4q, 5q, 6, 7p, 8, 9, 10, 11, 12q, 13, 14, 16q, 17, and 20, (2) reduced SNP copy number at FAT gene (4q35) in 75% of SS cases, and (3) the separation of all SS cases from normal control samples by SNP LOH gene clusters at chromosome regions of 9q31q34, 10p11q26, and 13q11q12. These findings provide some intriguing information for our current understanding of the molecular pathogenesis of this tumour and suggest the possibility of presence of functional SNP LOH in SS tumour cells.

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