Diagnosis and Pathobiology
Franklyn De Silva, Jane Alcorn in The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
About 50% of human cancers have mutations in chromatin proteins [283]. Approximately 6 billion coding and noncoding DNA bases are swaddled around ~30 million nucleosomes assembling an enormous, delicate, and intricately controlled macromolecular complex called ‘chromatin' [283]. The two major regions of chromatin include euchromatin (active genes containing an area with a relatively open configuration), and heterochromatin (late to replicate and highly condensed inactive gene containing area) [302]. Heterochromatin can be further separated into facultative heterochromatin, which encompasses repressed genes in a cell type-specific manner, and constitutive heterochromatin, which mainly encompasses repetitive sequences and transposons positioned at constant areas in different types of cells (e.g., pericentromeric regions) that can be transcribed at minute levels [323]. DNA and histone protein modifications, histone variants, components reading such modifications, noncoding RNAs, chromatin architectural proteins, and components remodeling chromatin, among others, are responsible for regulating the formation and maintenance of heterochromatin [323].
The Role of Epigenetics in Breast Cancer: Implications for Diagnosis, Prognosis, and Treatment
Brian Leyland-Jones in Pharmacogenetics of Breast Cancer, 2020
Along with methylation, posttranslational modification of histones plays an important role in epigenetics. Histone proteins associate with DNA to form nucleosomes, permitting large amounts of DNA to be neatly packaged into the nucleus. There are two configurations of chromatin, heterochromatin and euchromatin. Heterochromatin is condensed and transcriptionally inactive, while euchromatin has an “open” configuration and is favorable for gene transcription (Fig.2). The N-terminal tails of histones “stick out” of the nucleosome and are subject to posttranslational modification such as acetylation, phosphorylation, methylation, ubiquitination, and sumoylation (2,4,7,15). The pattern of histone modification creates a “code,” which is read by proteins involved in chromatin remodeling and the dynamics of gene transcription (6,11). Acetylation and deacteylation are the most common types of histone modification. Histone deacetylases (HDACs) are a class of enzymes that remove acetyl groups from a ε-N-acetyl lysine amino acid on a histone. Its action is opposite to that of histone acetyltransferases (HATs). Deacetylation removes acetyl groups from histone tails, causing the histones to wrap more tightly around the DNA and interfering with transcription by blocking access to transcription factors. The overall result of histone deacetylation is a global (nonspecific) reduction in gene expression (Table 1).
General Biological Aspects of Oncogenesis
Pimentel Enrique in Oncogenes, 2020
An increased affinity of the chromatin of neoplastic cells for chromatin dyes has been used for almost a century as a valuable criterion for the histological diagnosis of cancer. Heterochromatin corresponds to the repressed, nonfunctional portions of the genome, whereas euchromatin corresponds to the derepressed, actively transcribing portions of the genome. A progressive heterochromatinization occurs in the nuclei of liver cells in the course of liver carcinogenesis induced by chemical agents.15 These morphological changes partially reflect quantitative and qualitative alterations occurring in the chromatin of liver cells during the sequential events of hepatocarcinogenesis, with appearance of new nonhistone protein species in both eu- and heterochromatin.16
Heterochromatin extension: a possible cytogenetic fate of primary amenorrhea along with normal karyotype
Published in Journal of Obstetrics and Gynaecology, 2022
Bishal Kumar Dey, Shanoli Ghosh, Ajanta Halder, Somajita Chakraborty, Sanchita Roy
The region of heterochromatin also acts as a key part in chromosome structure, histone modification and gene regulation. There is evidence from where we come to know that there may be displacement of heterochromatin from one chromosome to another. Perhaps, this displacement is helping in the extension of a particular chromosome at the heterochromatin portion of the long arm (Bannister and Kouzarides 2011). The mechanisms of spindle fibres, chromosome movement, meiosis crossover and change of sister chromatids are considered to be the integral region as heterochromatin for a chromosome. At the time of meiosis, there may be a change in area of synapses of homologous chromosomes in the polymorphic heterochromatin region. The heterochromatin in chromosomal polymorphism can also regulate gene expression by reversible transformation between heterochromatin (non-coding DNA sequences) and euchromatin (expressed DNA sequences) thus justifying certain clinical expression like short stature or PA. It was also postulated that defective histone protein methylation due to presence of heteromorphic variants may play a more crucial role in ovarian failure. Association of heterochromatin polymorphism with ovarian dysgenesis may be a reason for the occurrence of PA. For that, we need to study on a greater number of patients on the basis of their nucleosome’s functionality and heteromorphic polymorphism by sequencing.
The γH2AX DSB marker may not be a suitable biodosimeter to measure the biological MRT valley dose
Published in International Journal of Radiation Biology, 2021
Jessica A. Ventura, Jacqueline F. Donoghue, Cameron J. Nowell, Leonie M. Cann, Liam R. J. Day, Lloyd M. L. Smyth, Helen B. Forrester, Peter A. W. Rogers, Jeffrey C. Crosbie
Our key finding is that γH2AX biodosimetry may not be a suitable method to measure the biological MRT valley dose due to the non-linear dose response observed in both in vitro and in vivo settings. However, additional studies that involve larger sample sizes are required to confirm this finding. We propose 2 theories that may explain the non-linearity: 1) heterochromatin decondensation and DSB movement, 2) intercellular communication and RIBE. The non-linear dose response observed in this study contradicts the assumption that radiation risk is proportional to radiation dose. Our findings point to novel MRT radiobiology and therefore our proposed theories require further investigation through techniques such as comet assay and qDSB-seq to determine absolute number of DSBs compared to γH2AX foci numbers established in this study, and time-lapse microscopy to monitor migration of DSBs from heterochromatin domains to ‘chromatin holes’. These studies could provide further clues to establish the biological and cellular communication mechanisms that drive the normal tissue sparing effect, a key attribute of MRT.
An expert overview of emerging therapies for acute myeloid leukemia: novel small molecules targeting apoptosis, p53, transcriptional regulation and metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Kapil Saxena, Marina Konopleva
Histones (H2A, H2B, H3, and H4) are proteins that assemble as an octamer (two of each) around which DNA wraps to form a nucleosome, the functional subunit of chromatin [82]. Chromatin typically exists in one of two major states – euchromatin and heterochromatin. While heterochromatin is tightly packaged and thereby more sterically restricted from transcriptional machinery, euchromatin has a more open conformation that is less condensed and more accessible to transcriptional complexes [82,83]. The transition between different chromatin states is partially mediated by histone modification. A major type of histone modification is acetylation/deacetylation. Histone acetylation can attract scaffolding proteins and enzymes involved in transcription. Enzymes that acetylate histones are termed histone acetyltransferases (HATs), and those that remove acetyl groups from histones are known as histone deacetylases (HDACs) [4,82–84]. Once histones are modified by acetylation, these changes need to be interpreted by other proteins for transcriptional regulation. Proteins that contain bromodomain (BRD) structures represent a class of proteins that can ‘read’ histone acetylation sites and indirectly regulate RNA polymerase II-mediated transcription [82,85].
Related Knowledge Centers
- Centromere
- Constitutive Heterochromatin
- DNA
- DNA Condensation
- Gene Expression
- Osmium Tetroxide
- Electron Microscope
- DNA
- DNA Condensation
- Rna-Induced Transcriptional Silencing
- Position-Effect Variegation
- Repeated Sequence