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Diagnosis and Pathobiology
Published in Franklyn De Silva, Jane Alcorn, The Elusive Road Towards Effective Cancer Prevention and Treatment, 2023
Franklyn De Silva, Jane Alcorn
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].
Cytogenetics of Colorectal Cancer
Published in Leonard H. Augenlicht, Cell and Molecular Biology of Colon Cancer, 2019
Very little is known about the function of constitutive heterochromatin. Some of the functional and organizational aspects of C-banding have been reviewed.88,89 Recently, one of us (S.P.) has hypothesized that these C-band blocks might represent gene amplification.90
Proteomic approaches for cancer epigenetics research
Published in Expert Review of Proteomics, 2019
Dylan M. Marchione, Benjamin A. Garcia, John Wojcik
The histone code hypothesis is the viewpoint that collectively, the pattern of these modifications around a particular genetic locus represents a set of instructions that are interpretable by chromatin-interacting (‘reader’) proteins, and perhaps one day by human investigators [7–9]. Indeed, certain histone modifications have been clearly associated with specific functions: histone H3K4me3 typically marks promoters of actively transcribed genes [10], H3K9me3 marks constitutive heterochromatin [11], H3K27me3 marks facultative heterochromatin [12], and H3K27ac marks active enhancers [13]. Current approaches to decipher the histone code are not unlike those which are used to decipher any other unknown language: the strategy favored by descriptive linguists is to (1) define the lexicon and (2) characterize the grammar. In this case, the lexicon is the entire catalog of histone modifications that can be utilized by cells. The grammar, then, is the principle of organization that dictates when specific modifications are used and how they relate to each other. MS is a uniquely well-suited approach to achieve both of these aims: targeted MS analyses have been used to discover novel histone PTMs such as crotonylation [14], 2-hydroxyisobutyrylation [15], and benzoylation [16], and middle-down and top-down proteomics analyses have been used to systematically catalog recurrent PTM combinations [17–20].
Increased stress and altered expression of histone modifying enzymes in brain are associated with aberrant behaviour in vitamin B12 deficient female mice
Published in Nutritional Neuroscience, 2020
Shampa Ghosh, Jitendra Kumar Sinha, Nitin Khandelwal, Sumana Chakravarty, Arvind Kumar, Manchala Raghunath
The enzyme SUV420H1 is known to catalyse the methylation of the histone H4 at Lysine 20 position. It is well established that SUV420H1 acts exclusively in constitutive heterochromatin maintenance. However, a study has shown that it also participates actively in transcriptional regulation affecting glucocorticoid receptor target gene expression.44 Therefore, it can be surmised that upregulation of SUV420H1 in the brain of severely deficient B12R+ mice (Fig. 5) is reflective of the alterations of epigenetic signature precipitating into increased stress observed in them that we had reported earlier.13 However, there are no studies elucidating the role of SUV420H1 in the brain and future studies on knockout models will shed light on this.
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
Reviewing the works of last decade, we have noticed that we have similar numerical and structural abnormalities found in the patients with PA (Table 3). Our previous study which was conducted by Ghosh et al. revealed 14% cases with structural chromosomal anomalies, out of 150 primary amenorrheic females and single case with heterochromatin extension for chromosome 9 (9qh+) along with normal karyotype. But in this present study, we found heterochromatin extension not only for 9qh+ but also for 16qh+. We found a case of age 14 with PA having 46, XX, 9qh+ karyotype with utero-vaginal abnormalities (Müllerian agenesis, hypoplastic ovaries, vaginal hypoplasia, etc.). For normal karyotype with extended heterochromatin, only FSH (p < .05) and TSH (p < .05) varied significantly. The increase in level of gonadotropins (FSH and LH) is higher in case of Turner’s syndrome karyotype with PA associated with increase in heterochromatin region. Perhaps, the concentration of TSH becomes elevated due to the neuro-endocrinological problems that may not be directly associated with PA. Analysis at the molecular level, may be needed to unveil any relationship between heteromorphism and PA taking in to consideration, the more crucial cellular effects of heterochromatin than previously thought. Chromosomal polymorphic variations, consisting of highly repetitive sequences of satellite DNA that do not encode any significant protein are considered to be normal variant. But chromosomal polymorphisms may cause certain clinical effects, such as infertility and recurrent miscarriages that comes from the data of recent studies (An et al. 2016). When infertility and adverse reproductive outcomes are found to be associated with karyotypic presentation with extended heteromorphic regions, it is not accurate to consider heteromorphic variants as being normal structural chromosomal aberrations. With refined molecular techniques, genes for fertility and viability are thought to reside in heterochromatin. DNA sequence analysis of human chromosome 9 has shown that it is highly structurally polymorphic with many intra-chromosomal and inter-chromosomal duplications. In response to environmental stress, there may be transcriptional activation of constitutive heterochromatin domains that lead to altered regulation of the genome and cause aberrations in chromosome pairing and cell division.