scholarly journals Role of Epigenetics in Cardiac Development and Congenital Diseases

2018 ◽  
Vol 98 (4) ◽  
pp. 2453-2475 ◽  
Author(s):  
Thomas Moore-Morris ◽  
Patrick Piet van Vliet ◽  
Gregor Andelfinger ◽  
Michel Puceat
Keyword(s):  
Cell Fate ◽  
Cardiac Development ◽  
Current Knowledge ◽  
Heart Diseases ◽  
Three Dimensional ◽  
Congenital Diseases ◽  
Heart Formation ◽  
Fate Decision ◽  
Essential Knowledge ◽  
The Impact

The heart is the first organ to be functional in the fetus. Heart formation is a complex morphogenetic process regulated by both genetic and epigenetic mechanisms. Congenital heart diseases (CHD) are the most prominent congenital diseases. Genetics is not sufficient to explain these diseases or the impact of them on patients. Epigenetics is more and more emerging as a basis for cardiac malformations. This review brings the essential knowledge on cardiac biology of development. It further provides a broad background on epigenetics with a focus on three-dimensional conformation of chromatin. Then, we summarize the current knowledge of the impact of epigenetics on cardiac cell fate decision. We further provide an update on the epigenetic anomalies in the genesis of CHD.

scholarly journals The Potential of Gamma Secretase as a Therapeutic Target for Cardiac Diseases

2021 ◽  
Vol 11 (12) ◽  
pp. 1294
Author(s):  
Sujoita Sen ◽  
Logan Hallee ◽  
Chi Keung Lam
Keyword(s):  
Therapeutic Target ◽  
Cardiac Development ◽  
Current Knowledge ◽  
Heart Diseases ◽  
Human Life ◽  
Heart Association ◽  
Therapeutic Interventions ◽  
Cardiac Diseases ◽  
Gamma Secretase ◽  
Protease Enzyme

Heart diseases are some of the most common and pressing threats to human health worldwide. The American Heart Association and the National Institute of Health jointly work to annually update data on cardiac diseases. In 2018, 126.9 million Americans were reported as having some form of cardiac disorder, with an estimated direct and indirect total cost of USD 363.4 billion. This necessitates developing therapeutic interventions for heart diseases to improve human life expectancy and economic relief. In this review, we look into gamma-secretase as a potential therapeutic target for cardiac diseases. Gamma-secretase, an aspartyl protease enzyme, is responsible for the cleavage and activation of a number of substrates that are relevant to normal cardiac development and function as found in mutation studies. Some of these substrates are involved in downstream signaling processes and crosstalk with pathways relevant to heart diseases. Most of the substrates and signaling events we explored were found to be potentially beneficial to maintain cardiac function in diseased conditions. This review presents an updated overview of the current knowledge on gamma-secretase processing of cardiac-relevant substrates and seeks to understand if the modulation of gamma-secretase activity would be beneficial to combat cardiac diseases.

scholarly journals Autophagy Roles in Genome Maintenance

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1793 ◽  
Author(s):  
Susanna Ambrosio ◽  
Barbara Majello
Keyword(s):  
Dna Damage ◽  
Cell Fate ◽  
Dna Damage Response ◽  
Current Knowledge ◽  
Response To Therapy ◽  
Genome Integrity ◽  
Genome Maintenance ◽  
Damage Response ◽  
Cancer Cell Survival ◽  
Fate Decision

In recent years, a considerable correlation has emerged between autophagy and genome integrity. A range of mechanisms appear to be involved where autophagy participates in preventing genomic instability, as well as in DNA damage response and cell fate decision. These initial findings have attracted particular attention in the context of malignancy; however, the crosstalk between autophagy and DNA damage response is just beginning to be explored and key questions remain that need to be addressed, to move this area of research forward and illuminate the overall consequence of targeting this process in human therapies. Here we present current knowledge on the complex crosstalk between autophagy and genome integrity and discuss its implications for cancer cell survival and response to therapy.

scholarly journals Hypoxia Pathway Proteins in Normal and Malignant Hematopoiesis

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 155 ◽  
Author(s):  
Ben Wielockx ◽  
Tatyana Grinenko ◽  
Peter Mirtschink ◽  
Triantafyllos Chavakis
Keyword(s):  
Cell Fate ◽  
Current Knowledge ◽  
Hypoxia Inducible Factor ◽  
Adult Life ◽  
Low Oxygen ◽  
Hematopoietic Stem ◽  
Metabolism Regulation ◽  
Hsc Niche ◽  
Hif Pathway ◽  
The Impact

The regulation of oxygen (O2) levels is crucial in embryogenesis and adult life, as O2 controls a multitude of key cellular functions. Low oxygen levels (hypoxia) are relevant for tissue physiology as they are integral to adequate metabolism regulation and cell fate. Hence, the hypoxia response is of utmost importance for cell, organ and organism function and is dependent on the hypoxia-inducible factor (HIF) pathway. HIF pathway activity is strictly regulated by the family of oxygen-sensitive HIF prolyl hydroxylase domain (PHD) proteins. Physiologic hypoxia is a hallmark of the hematopoietic stem cell (HSC) niche in the bone marrow. This niche facilitates HSC quiescence and survival. The present review focuses on current knowledge and the many open questions regarding the impact of PHDs/HIFs and other proteins of the hypoxia pathway on the HSC niche and on normal and malignant hematopoiesis.

The Complementary Effect of Mechanical and Chemical Stimuli on the Neural Differentiation of Mesenchymal Stem Cells

2012 ◽  
Author(s):  
Chun Liu ◽  
Seungik Baek ◽  
Christina Chan
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Fate ◽  
Neural Differentiation ◽  
Late Phase ◽  
Tissue Repair And Regeneration ◽  
Chemical Stimuli ◽  
Fate Decision ◽  
The Impact ◽  
Promising Source

Mesenchymal stem cells (MSCs), derived from bone marrow stroma, are a promising source for tissue repair and regeneration, due to their excellent abilities for proliferation and multipotent differentiation. While accumulated evidences during the past decade have shown that MSCs are able to differentiate into osteoblasts, chondrocytes, myoblasts and adipocytes, more recent research suggest their potential in neuronal differentiation [1]. Chemical stimuli, including growth factors, hormones, and other regulatory molecules, are used traditionally to direct MSC differentiation. Our group has previously shown that the intracellular second messenger, cAMP, is able to initiate early phase neuron-like morphology changes and late phase neural differentiation in MSCs [2]. Studies using chemical stimuli alone, however, have shown limited success in differentiating MSCs to mature neurons, thereby suggesting other factors are necessary for this process. In recent years, interest has grown on the impact of mechanical stimulation, such as stiffness, surface topography, and mechanical stretching, on cell fate decision [3].

scholarly journals Three-dimensional cell neighbourhood impacts differentiation in the inner mass cells of the mouse blastocyst

2017 ◽  
Author(s):  
Sabine C. Fischer ◽  
Elena Corujo-Simón ◽  
Joaquín Lilao-Garzón ◽  
Ernst H. K. Stelzer ◽  
Silvia Muñoz-Descalzo
Keyword(s):  
Cell Fate ◽  
Inner Cell Mass ◽  
Cell Mass ◽  
Three Dimensional ◽  
Mouse Blastocyst ◽  
Blastocyst Development ◽  
Cell Position ◽  
Fate Decision ◽  
Early Mouse ◽  
Dimensional Cell

AbstractDuring mammalian blastocyst development, inner cell mass (ICM) cells differentiate into epiblast (Epi) or primitive endoderm (PrE). These two fates are characterised by the transcription factors NANOG and GATA6, respectively. Here, we present quantitative three-dimensional single cell-based neighbourhood analyses to investigate the spatial distribution of NANOG and GATA6 expression in the ICM of the mouse blastocyst. The cell neighbourhood is characterised by the expression levels of the fate markers in the surrounding cells, together with the number of surrounding cells and cell position. We find that cell neighbourhoods are established in early blastocysts and different for cells expressing different levels of NANOG and GATA6. Highest NANOG expressing cells occupy specific positions within the ICM and are surrounded by 9 neighbours, while GATA6 expressing cells cluster according to their GATA6 levels. The analysis of mutants reveals that NANOG local neighbourhood is regulated by GATA6.Summary statementThree-dimensional cell neighbourhood, which includes fate marker levels, number of neighbouring cells and cell position, determines cell fate decision in early mouse embryos.

Collagen hydroxylysine glycosylation: non-conventional substrates for atypical glycosyltransferase enzymes

2021 ◽  
Author(s):  
Francesca De Giorgi ◽  
Marco Fumagalli ◽  
Luigi Scietti ◽  
Federico Forneris
Keyword(s):  
Current Knowledge ◽  
Three Dimensional ◽  
Major Constituent ◽  
Post Translational Modifications ◽  
Current State ◽  
Lysine Residues ◽  
Collagen Molecules ◽  
Triple Helices ◽  
The Impact

Collagen is a major constituent of the extracellular matrix (ECM) that confers fundamental mechanical properties to tissues. To allow proper folding in triple-helices and organization in quaternary super-structures, collagen molecules require essential post-translational modifications (PTMs), including hydroxylation of proline and lysine residues, and subsequent attachment of glycan moieties (galactose and glucose) to specific hydroxylysine residues on procollagen alpha chains. The resulting galactosyl-hydroxylysine (Gal-Hyl) and less abundant glucosyl-galactosyl-hydroxylysine (Glc-Gal-Hyl) are amongst the simplest glycosylation patterns found in nature and are essential for collagen and ECM homeostasis. These collagen PTMs depend on the activity of specialized glycosyltransferase enzymes. Although their biochemical reactions have been widely studied, several key biological questions about the possible functions of these essential PTMs are still missing. In addition, the lack of three-dimensional structures of collagen glycosyltransferase enzymes hinders our understanding of the catalytic mechanisms producing this modification, as well as the impact of genetic mutations causing severe connective tissue pathologies. In this mini-review, we summarize the current knowledge on the biochemical features of the enzymes involved in the production of collagen glycosylations and the current state-of-the-art methods for the identification and characterization of this important PTM.

scholarly journals Maternal vitamin D deficiency impairs heart formation in mouse offspring through a change in 3D-chromatin structure

2020 ◽  
Author(s):  
Eva M. Seipelt ◽  
Paul Bensadoun ◽  
Satish Sati ◽  
Charlène Couturier ◽  
Julien Astier ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Deficiency ◽  
Molecular Mechanisms ◽  
Heart Diseases ◽  
Left Ventricular ◽  
Childbearing Age ◽  
Congenital Diseases ◽  
Maternal Vitamin ◽  
Two Generations ◽  
Heart Formation

AbstractThe origins of congenital heart diseases, the most common congenital diseases are still largely unknown. Environmental factors are now emerging as major causes of these diseases. Vitamin D deficiency has become a public health burden, notably for childbearing age, pregnant and breastfeeding women. Since maternal 25-hydroxyvitamin D (25(OH)D) determined fetal and neonatal 25(OH)D status, foetuses exposed to insufficient levels of vitamin D, may feature developmental defects.Herein, we investigated the effects of maternal vitamin D deficiency on cardiovascular defects in early and later life of offsprings in two generations as well as the molecular mechanisms underlying vitamin D effect.Eight weeks before and during pregnancy, C57BL/6JRj female mice received a sufficient or vitamin D deficient diet ((1.0 IU/g in control vs 0.0 IU/g in Vitamin D Deficient (VDD) group). E16.5 Embryos of maternal VDD diet featured hypertrophic heart revealed by a thicker left ventricular (LV) wall and septum. RNAseq analysis of LV revealed 1555 transcripts differentially expressed in the VDD group and among them cardiac transcription factors and constitutive cardiac genes (tbx5, gata4, myl2). Anti-Vitamin D receptor (VDR) Chip-seq from chromatin of E16.5 LV uncovered different targeting of tbx5 and tbx3 loci by VDR in the VDD vs control embryos. Anti-CTCF ChIP-loop experiments focusing on the Tbx3 and Tbx5 loci uncovered a change in the Topology Associated Domains associated with these loci.Echocardiography of 2-months-old VDD offspring revealed a significantly thicker left ventricle and increased fractional shortening while 6-months-old mice featured cardiac decompensation and in turn failing LV.Maternal vitamin D deficiency severely affects heart formation following a change in chromatin conformation on cardiac gene loci and impacts function of adult hearts in two generations. These defects are likely to be at the origin of cardiovascular diseases in the adulthood.

scholarly journals Modular HUWE1 architecture serves as hub for degradation of cell-fate decision factors

2020 ◽  
Author(s):  
Moritz Hunkeler ◽  
Cyrus Y. Jin ◽  
Michelle W. Ma ◽  
Daan Overwijn ◽  
Julie K. Monda ◽  
...  
Keyword(s):  
Cell Fate ◽  
Three Dimensional ◽  
Cellular Stress Response ◽  
Cell Fate Decision ◽  
Decision Factors ◽  
Link Functions ◽  
Wide Range ◽  
Essential Enzyme ◽  
Fate Decision ◽  
Molecular Picture

SummaryHECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors including Mcl1, p53, DDIT4, and Myc. As a step toward understanding regulation of HUWE1 engagement with its diverse substrates, we present here the cryo-EM structure of HUWE1, offering a first complete molecular picture of a HECT ubiquitin ligase. The ~4400 amino acid residue polypeptide forms an alpha solenoid-shaped assembly with a central pore decorated with protein interaction modules. This modularity enables HUWE1 to target a wide range of substrates for destruction. The locations of human mutations associated with severe neurodevelopmental disorders link functions of this essential enzyme with its three-dimensional organization.

scholarly journals Three-dimensional model of glioblastoma by co-culturing tumor stem cells with human brain organoids

Biology Open ◽  
2021 ◽  
Vol 10 (2) ◽  
Author(s):  
Roberta Azzarelli ◽  
Michela Ori ◽  
Anna Philpott ◽  
Benjamin D. Simons
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Cell Biology ◽  
Three Dimensional ◽  
3D Culture ◽  
Significant Degree ◽  
Culture Conditions ◽  
Three Dimensional Model ◽  
The Impact

ABSTRACT Emerging three-dimensional (3D) cultures of glioblastoma are becoming powerful models to study glioblastoma stem cell behavior and the impact of cell–cell and cell–microenvironment interactions on tumor growth and invasion. Here we describe a method for culturing human glioblastoma stem cells (GSCs) in 3D by co-culturing them with pluripotent stem cell-derived brain organoids. This requires multiple coordinated steps, including the generation of cerebral organoids, and the growth and fluorescence tagging of GSCs. We highlight how to recognize optimal organoid generation and how to efficiently mark GSCs, before describing optimized co-culture conditions. We show that GSCs can efficiently integrate into brain organoids and maintain a significant degree of cell fate heterogeneity, paving the way for the analysis of GSC fate behavior and lineage progression. These results establish the 3D culture system as a viable and versatile GBM model for investigating tumor cell biology and GSC heterogeneity. This article has an associated First Person interview with the first author of the paper.

scholarly journals Replacing reprogramming factors with antibodies selected from autocrine antibody libraries

2017 ◽  
Author(s):  
Joel W. Blanchard ◽  
Jia Xie ◽  
Nadja El-Mecharrafie ◽  
Simon Gross ◽  
Sohyon Lee ◽  
...  
Keyword(s):  
Cell Fate ◽  
Current Knowledge ◽  
Differentiated Cells ◽  
Extracellular Signaling ◽  
Nuclear Factors ◽  
Antibody Libraries ◽  
Membrane Bound ◽  
Reprogramming Factors ◽  
Induced Pluripotent ◽  
The Impact

SummarySignaling pathways initiated at the membrane establish and maintain cell fate during development and can be harnessed in the nucleus to generate induced pluripotent stem cells (iPSCs) from differentiated cells. Yet, the impact of extracellular signaling on reprogramming to pluripotency has not been systematically addressed. Here, we screen a lentiviral library encoding ˜100 million secreted and membrane-bound antibodies and identify multiple antibodies that can replace Sox2/c-Myc or Oct4 during reprogramming. We show that one Sox2-replacing antibody initiates reprogramming by antagonizing the membrane-associated protein Basp1, thereby inducing nuclear factors WT1 and Esrrb/Lin28 independent of Sox2. By successively manipulating this pathway we identify three new methods to generate iPSCs. This study expands current knowledge of reprogramming methods and mechanisms and establishes unbiased selection from autocrine antibody libraries as a powerful orthogonal platform to discover new biologics and pathways regulating pluripotency and cell fate.

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