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 Metabolism navigates neural cell fate in development, aging and neurodegeneration

2021 ◽  
Vol 14 (8) ◽  
Author(s):  
Larissa Traxler ◽  
Jessica Lagerwall ◽  
Sophie Eichhorner ◽  
Davide Stefanoni ◽  
Angelo D'Alessandro ◽  
...  
Keyword(s):  
Cell Fate ◽  
Neural Development ◽  
Metabolic Pathways ◽  
Neural Cell ◽  
Adult Brain ◽  
Metabolic States ◽  
Age Dependent ◽  
Phosphorylation Mechanism ◽  
And Function ◽  
Neural Cell Fate

ABSTRACT An uninterrupted energy supply is critical for the optimal functioning of all our organs, and in this regard the human brain is particularly energy dependent. The study of energy metabolic pathways is a major focus within neuroscience research, which is supported by genetic defects in the oxidative phosphorylation mechanism often contributing towards neurodevelopmental disorders and changes in glucose metabolism presenting as a hallmark feature in age-dependent neurodegenerative disorders. However, as recent studies have illuminated roles of cellular metabolism that span far beyond mere energetics, it would be valuable to first comprehend the physiological involvement of metabolic pathways in neural cell fate and function, and to subsequently reconstruct their impact on diseases of the brain. In this Review, we first discuss recent evidence that implies metabolism as a master regulator of cell identity during neural development. Additionally, we examine the cell type-dependent metabolic states present in the adult brain. As metabolic states have been studied extensively as crucial regulators of malignant transformation in cancer, we reveal how knowledge gained from the field of cancer has aided our understanding in how metabolism likewise controls neural fate determination and stability by directly wiring into the cellular epigenetic landscape. We further summarize research pertaining to the interplay between metabolic alterations and neurodevelopmental and psychiatric disorders, and expose how an improved understanding of metabolic cell fate control might assist in the development of new concepts to combat age-dependent neurodegenerative diseases, particularly Alzheimer's disease.

scholarly journals Software tools for visualizing Hi-C data

2016 ◽  
Author(s):  
Galip Gürkan Yardımcı ◽  
William Stafford Noble
Keyword(s):  
High Throughput ◽  
Three Dimensional ◽  
Software Tools ◽  
Genome Browser ◽  
Visualization Tool ◽  
3D Genome ◽  
Accurate Interpretation ◽  
Three Dimensional Configuration ◽  
And Function ◽  
The Relationship

AbstractRecently developed, high-throughput assays for measuring the three-dimensional configuration of DNA in the nucleus have provided unprecedented insights into the relationship between DNA 3D configuration and function. However, accurate interpretation of data from assays such as ChIA-PET and Hi-C is challenging because the data is large and cannot be easily rendered using a standard genome browser. In particular, an effective Hi-C visualization tool must provide a variety of visualization modes and be capable of viewing the data in conjunction with existing, complementary data. We review a number of such software tools that have been described recently in the literature, focusing on tools that do not require programming expertise on the part of the user. In particular, we describe HiBrowse, Juicebox, my5C, the 3D Genome Browser, and the Epigenome Browser, outlining their complementary functionalities and highlighting which types of visualization tasks each tool is best designed to handle.

Extracellular matrix (ECM) microstructural composition regulates local cell-ECM biomechanics and fundamental fibroblast behavior: a multidimensional perspective

2005 ◽  
Vol 98 (5) ◽  
pp. 1909-1921 ◽  
Author(s):  
A. M. Pizzo ◽  
K. Kokini ◽  
L. C. Vaughn ◽  
B. Z. Waisner ◽  
S. L. Voytik-Harbin
Keyword(s):  
Extracellular Matrix ◽  
Cell Fate ◽  
Three Dimensional ◽  
Local Strain ◽  
Β1 Integrin ◽  
Ecm Remodeling ◽  
Surface Areas ◽  
Local Cell ◽  
And Function

The extracellular matrix (ECM) provides the principal means by which mechanical information is communicated between tissue and cellular levels of function. These mechanical signals play a central role in controlling cell fate and establishing tissue structure and function. However, little is known regarding the mechanisms by which specific structural and mechanical properties of the ECM influence its interaction with cells, especially within a tissuelike context. This lack of knowledge precludes formulation of biomimetic microenvironments for effective tissue repair and replacement. The present study determined the role of collagen fibril density in regulating local cell-ECM biomechanics and fundamental fibroblast behavior. The model system consisted of fibroblasts seeded within collagen ECMs with controlled microstructure. Confocal microscopy was used to collect multidimensional images of both ECM microstructure and specific cellular characteristics. From these images temporal changes in three-dimensional cell morphology, time- and space-dependent changes in the three-dimensional local strain state of a cell and its ECM, and spatial distribution of β1-integrin were quantified. Results showed that fibroblasts grown within high-fibril-density ECMs had decreased length-to-height ratios, increased surface areas, and a greater number of projections. Furthermore, fibroblasts within low-fibril-density ECMs reorganized their ECM to a greater extent, and it appeared that β1-integrin localization was related to local strain and ECM remodeling events. Finally, fibroblast proliferation was enhanced in low-fibril-density ECMs. Collectively, these results are significant because they provide new insight into how specific physical properties of a cell’s ECM microenvironment contribute to tissue remodeling events in vivo and to the design and engineering of functional tissue replacements.

scholarly journals Fgfr2 is integral for bladder mesenchyme patterning and function

2015 ◽  
Vol 308 (8) ◽  
pp. F888-F898 ◽  
Author(s):  
K. A. Walker ◽  
Y. Ikeda ◽  
I. Zabbarova ◽  
C. M. Schaefer ◽  
D. Bushnell ◽  
...  
Keyword(s):  
Cell Fate ◽  
Ex Vivo ◽  
Smooth Muscle Actin ◽  
Three Dimensional ◽  
Growth Factor Receptor ◽  
Immunoblot Analysis ◽  
Type Ia ◽  
And Function ◽  
Passive Stretch

While urothelial signals, including sonic hedgehog (Shh), drive bladder mesenchyme differentiation, it is unclear which pathways within the mesenchyme are critical for its development. Studies have shown that fibroblast growth factor receptor (Fgfr)2 is necessary for kidney and ureter mesenchymal development. The objective of the present study was to determine the role of Fgfr2 in the bladder mesenchyme. We used Tbx18cre mice to delete Fgfr2 in the bladder mesenchyme ( Fgfr2 BM−/−). We performed three-dimensional reconstructions, quantitative real-time PCR, in situ hybridization, immunolabeling, ELISAs, immunoblot analysis, void stain on paper, ex vivo bladder sheet assays, and in vivo decerebrated cystometry. Compared with control bladders, embryonic day 16.5 (E16.5) Fgfr2 BM−/− bladders had thin muscle layers with less α-smooth muscle actin and thickened lamina propria with increased collagen type Ia and IIIa that intruded into the muscle. The reciprocal changes in mutant layer thicknesses appeared partly due to a cell fate switch. From postnatal days 1 to 30, Fgfr2 BM−/− bladders demonstrated progressive muscle loss and increased collagen expression. Postnatal Fgfr2 BM−/− bladder sheets exhibited decreased agonist-mediated contractility and increased passive stretch tension versus control bladder sheets. Cystometry revealed high baseline and threshold pressures and shortened intercontractile intervals in Fgfr2 BM−/− versus control bladders. Mechanistically, whereas Shh expression appeared normal, mRNA and protein readouts of hedgehog activity were increased in E16.5 Fgfr2 BM−/− versus control bladders. Moreover, E16.5 Fgfr2 BM−/− bladders exhibited higher levels of Cdo and Boc, hedgehog coreceptors that enhance sensitivity to Shh, compared with control bladders. In conclusion, loss of Fgfr2 in the bladder mesenchyme leads to abnormal bladder morphology and decreased compliance and contractility.

scholarly journals Disruptions of Global and Jagged1-Mediated Notch Signaling Affect Thyroid Morphogenesis in the Zebrafish

Endocrinology ◽  
2012 ◽  
Vol 153 (11) ◽  
pp. 5645-5658 ◽  
Author(s):  
Patrizia Porazzi ◽  
Federica Marelli ◽  
Francesca Benato ◽  
Tiziana de Filippis ◽  
Davide Calebiro ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Notch Pathway ◽  
Genetic Alterations ◽  
Human Thyroid ◽  
Thyroid Cells ◽  
Notch Intracellular Domain ◽  
Molecular Events ◽  
And Function ◽  
Thyroid Development

Abstract The mechanisms underlying the early steps of thyroid development are largely unknown. In search for novel candidate genes implicated in thyroid function, we performed a gene expression analysis on thyroid cells revealing that TSH regulates the expression of several elements of the Notch pathway, including the ligand Jagged1. Because the Notch pathway is involved in cell-fate determination of several foregut-derived endocrine tissues, we tested its contribution in thyroid development using the zebrafish, a teleost model recapitulating the mammalian molecular events during thyroid development. Perturbing the Notch signaling (e.g. mib mutants, γ-secretase inhibition, or Notch intracellular domain overexpression), we obtained evidence that this pathway has a biological role during the earlier phases of thyroid primordium induction, limiting the number of cells that proceed to a specialized fate and probably involving actions from surrounding tissues. Moreover, we were able to confirm the expression of Jagged1 during different phases of zebrafish thyroid development, as well as in mouse and human thyroid tissues. The two orthologues to the single jagged1 gene (JAG1) in humans, jag1a and jag1b, are expressed with different spatiotemporal patterns in the developing zebrafish thyroid. Both jag1a and jag1b morphants, as well as jag1b mutant fish line, display thyroid hypoplasia and impaired T4 production; this thyroid phenotype was rescued by coinjection of human JAG1 mRNA. In conclusion, Notch pathway is involved in the early steps of thyroid morphogenesis, and Jagged1-Notch signal is required for zebrafish thyroid development and function. Thus, genetic alterations affecting the Notch pathway may confer susceptibility for thyroid dysgenesis.

scholarly journals EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

2021 ◽  
Vol 22 (20) ◽  
pp. 11292
Author(s):  
Barbara Kunzler Souza ◽  
Natalia Hogetop Freire ◽  
Mariane Jaeger ◽  
Caroline Brunetto de Farias ◽  
Algemir L. Brunetto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Brain Cancer ◽  
Adult Brain ◽  
Post Translational Modifications ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Cancer Types

Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors.

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 G9a/GLP-Sensitivity of H3K9me2 Demarcates Two Types of Genomic Compartments

2020 ◽  
Author(s):  
Zixiang Yan ◽  
Luzhang Ji ◽  
Xiangru Huo ◽  
Qianfeng Wang ◽  
Yuwen Zhang ◽  
...  
Keyword(s):  
Genome Organization ◽  
Molecular Mechanisms ◽  
Three Dimensional ◽  
Embryonic Stem ◽  
Nuclear Lamina ◽  
Hierarchical Architecture ◽  
Functional Roles ◽  
3D Genome ◽  
Differentiated Cells ◽  
Mouse Hepatocytes

AbstractIn the nucleus, chromatin is folded into hierarchical architecture that is tightly linked to various nuclear functions. However, the underlying molecular mechanisms that confer these architectures remain incompletely understood. Here, we investigated the functional roles of H3 lysine 9 dimethylation (H3K9me2), one of the abundant histone modifications, in three-dimensional (3D) genome organization. Unlike mouse embryonic stem cells (mESCs), inhibition of methyltransferases G9a and GLP in differentiated cells eliminated H3K9me2 predominantly at A-type (active) genomic compartments, and the level of residual H3K9me2 modification was strongly associated with genomic compartments in differentiated cells. Furthermore, chemical inhibition of G9a/GLP in mouse hepatocytes led to the decreased chromatin-nuclear lamina interactions mainly at G9a/GLP sensitive regions (GSRs), the increased degree of genomic compartmentalization, and the up-regulation of hundreds of genes that were associated with alterations of the 3D chromatin. Collectively, our data demonstrated essential roles of H3K9me2 in 3D genome organization.

Conformation of Ribosomes from Escherichia Coli

1974 ◽  
Vol 32 ◽  
pp. 210-211
Author(s):  
M. Boublik ◽  
W. Hellmann ◽  
F. Jenkins
Keyword(s):  
Binding Sites ◽  
Ribosomal Proteins ◽  
Fluorescent Dyes ◽  
Protein Biosynthesis ◽  
Three Dimensional ◽  
Spatial Arrangement ◽  
Dimensional Structure ◽  
Complete Understanding ◽  
And Function

The present knowledge of the three-dimensional structure of ribosomes is far too limited to enable a complete understanding of the various roles which ribosomes play in protein biosynthesis. The spatial arrangement of proteins and ribonuclec acids in ribosomes can be analysed in many ways. Determination of binding sites for individual proteins on ribonuclec acid and locations of the mutual positions of proteins on the ribosome using labeling with fluorescent dyes, cross-linking reagents, neutron-diffraction or antibodies against ribosomal proteins seem to be most successful approaches. Structure and function of ribosomes can be correlated be depleting the complete ribosomes of some proteins to the functionally inactive core and by subsequent partial reconstitution in order to regain active ribosomal particles.

Structure and function of neural networks in the retina

1988 ◽  
Vol 46 ◽  
pp. 26-27
Author(s):  
Peter Sterling
Keyword(s):  
Ganglion Cells ◽  
Three Dimensional ◽  
Structure And Function ◽  
Synaptic Connections ◽  
Visual Axis ◽  
One Dimensional ◽  
Cat Retina ◽  
Ultrathin Sections ◽  
And Function ◽  
Insight Into

The synaptic connections in cat retina that link photoreceptors to ganglion cells have been analyzed quantitatively. Our approach has been to prepare serial, ultrathin sections and photograph en montage at low magnification (˜2000X) in the electron microscope. Six series, 100-300 sections long, have been prepared over the last decade. They derive from different cats but always from the same region of retina, about one degree from the center of the visual axis. The material has been analyzed by reconstructing adjacent neurons in each array and then identifying systematically the synaptic connections between arrays. Most reconstructions were done manually by tracing the outlines of processes in successive sections onto acetate sheets aligned on a cartoonist's jig. The tracings were then digitized, stacked by computer, and printed with the hidden lines removed. The results have provided rather than the usual one-dimensional account of pathways, a three-dimensional account of circuits. From this has emerged insight into the functional architecture.

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