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Signal transduction and exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Brendan Egan, Adam P. Sharples
The tight packaging of DNA in chromatin must be unravelled before a gene can be transcribed. The packaging and unpackaging of DNA are known as chromatin remodelling and histone modifications are key mechanisms in the regulation of this process. Mapping of packaged and unpackaged DNA on a genome-wide scale has revealed that histone tail modifications are cell-specific and mark genes, transcription start sites and stretches of regulatory DNA, via which gene expression is regulated (53). Indeed, signal transduction pathways modulate chromatin remodelling by methylating (CH3, methyl group), acetylating (CH3CO, acetyl group) and phosphorylating histone proteins, especially in the tail regions of histones H3 and H4 (19, 20). The enzymes that catalyse these modifications include histone methyltransferases and histone demethylases as well as histone acetyltransferases and HDACs. The resultant modifications are abbreviated stating first the histone number, second the amino acid which is modified and finally the type of modification (ac stands for acetylation, me1, me2, m3 for methylation, dimethylation and trimethylation, respectively). For example, H3K27me3 refers to the trimethylation of lysine 27 (K is the one-letter abbreviation for lysine) of histone 3.
Diffuse Intrinsic Pontine Glioma
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Katherine E. Warren, Carolyn R. Freeman, Dannis G. van Vuurden
The histone mutations occurring in DIPG can be subclassified as H3.3 (encoded for by the H3F3A gene) or H3.1 (encoded for by the HIST1H3B gene) mutations. These gain-of-function mutations result in a lysine 27 to methionine substitution (H3K27M). While the details of the consequences of this substitution are still being uncovered, we know it ultimately leads to loss of histone trimethylation (reduced H3K27me3), which, in turn, interrupts the regulatory feedback loops to the polycomb repressive complex (PRC2).34 As a result, PRC2 is inhibited, leading to epigenetic silencing and broad dysregulation of transcription. PRC2 and the product of its catalytic activity, H3K27me3, are then potentially redirected and function in maintaining DIPG growth and activity.35 A recent study also demonstrated that, with loss of H3K27me3, increased H3K27M-K27ac heterotypic nucleosomes form; these acetylated histones are bound by bromodomain proteins, identifying a potential target for tumor inhibition.35
Weaver Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Located on chromosome 7q36.1, the enhancer of zeste, drosophila, homolog 2 gene (EZH2) comprises multiple alternative transcripts, the longest of which has 20 exons and encodes a 751-amino-acid histone methyltransferase (EZH2) with a critical SET [su(var)3–9, enhancer of zeste, trithorax] domain, a pre-SET CXC domain, and two additional SANT (Sw13, Ada2, N-cor TFIIIB) domains. EZH2 constitutes the catalytic subunit of the polycomb-repressive complex 2 (PRC2), which also includes additional core components SUZ12 (suppressor of zeste 12) and EED (embryonic ectoderm development). As a highly conserved epigenetic modifying complex, PRC2 induces trimethylation of histone H3 at lysine 27 (resulting in H3K27me3), which serves as an epigenetic signal for chromatin condensation and transcriptional repression and contributes to the regulation of chondrocyte proliferation and hypertrophy in the growth plate [9]. Functional loss of any of the components (i.e., EZH2, SUZ12, and EED) compromises the enzymatic activity of PRC2 and subsequent reduction of H3K27me3, leading to transcriptional activation of loci to which H3K27me3 is bound [10–12].
Epigenetic control of skin immunity
Published in Immunological Medicine, 2023
Currently, studies on the epigenetic environment in immune cells from patients with skin diseases, and its association with the relevant transcriptional factors are sparse. One study has reported histone mark signatures in PBMCs from psoriasis patients, showing decreased levels of global histone H4 acetylation compared to healthy controls [28]. However, they make no mention of the possible regulatory regions responsible for the observed quantitative changes in histone modification or the target genes affected. Thus, the detailed mechanisms by which the changes in histone modification regulate the expression of disease-related genes remain unelucidated. In another study, the overall degree of histone acetylation or methylation throughout genomic DNA is suggested to be an indicator of subsequent therapeutic response [29]. There is no difference in expression levels of H3K27me3 between healthy controls and untreated psoriasis patients, however, only those that responded to biological treatment exhibited increased H3K27me3 levels. Recently, the enhancer of zeste homolog 2 (EZH2), a writer of H3K27me3, in regulatory T cells (Tregs) has been focused on its function [30,31]. EZH2 is required for Tregs activation, and Foxp3-specific EZH2 inactivation is known to impair immune tolerance [32]. Although the cellular components in PBMCs that are responsible for the increase in H3K27me3 after biological treatment are unknown, the associations between cell-specific histone modification and therapeutic efficacy will be of considerable interest in the future.
Malignant peripheral nerve sheath tumor of the orbit: a case report and review of the literature
Published in Orbit, 2022
Kara E. Jones, Ami Patel, Mary G. Kunesh, Bradley A. Thuro
Of the reported cases of MPNSTs involving the orbit, histology showed myoxid or spindle cell subtypes; clinical presentation was similar in regard to clinical characteristics (Table 1). Interestingly, while every reported case with available immunohistochemistry was noted to be S-100 positive, our case was S-100 negative. Because this tumor was noted to be S-100 negative, and vimentin and bcl-2 positive, an additional consideration for differential diagnosis would be a dedifferentiated solitary fibrous tumor (SFT). A dedifferentiated SFT may lose the typical CD34 positivity in about 50% of cases,13 and our case also demonstrates CD-34 negativity. Vimentin and bcl-2 can be positive in both MPNSTs and dedifferentiated SFTs, although such characteristics are inconsistent with further dedifferentiation. Even STAT6 staining is often lost in dedifferentiated SFTs.13 Perhaps the most distinguishing factor for the tumor in this patient is the complete loss of H3K27me3. H3K27me3 refers to the trimethylation of lysine 27 of histone H3 which is normally constitutively expressed resulting in downward regulation of gene expression; its loss of function has been associated with a significant subset (34%) of MPNSTs.14 Thus, based on the suspected primary location of the upper extremity, the diagnosis was felt to be most consistent with MPNST.
Epigenetic changes involved in hydroquinone-induced mutations
Published in Toxin Reviews, 2021
Minjuan Zeng, Shaopeng Chen, Ke Zhang, Hairong Liang, Jie Bao, Yuting Chen, Shiheng Zhu, Wei Jiang, Hui Yang, Yixian Wei, Lihao Guo, Huanwen Tang
Histone methylation is different from DNA methylation, as it is simply a marker of gene repression. Trimethylation of lysine 9 and lysine 27 of histone 3 (H3K9me3 andH3K27me3) is also a silencing marker, but trimethylation of lysine 4 of histone 3 (H3K4me3) is an activation marker that results in increased gene expression. Mancini et al. (2017) detected a distinctive signature combining repressive H3K27me3 and activating H3K4me3, indicating a tendency toward a poised chromatin conformation in the HL-60 cell line treated with HQ. These alterations were lost after short-term treatments, while long-term treatment resulted in a gradual increase in H3K4me3 and stable H3K27me3, most likely indicating increased activation of gene expression. Li et al. (2018) reported that H3K4me3 modification was significantly enhanced in benzene-exposed workers and was positively associated with the extent of DNA damage. Furthermore, the H3K4me3 marker was enriched in the promoters of several DNA damage responsive (DDR) genes, including CRY1, ERCC2, and TP53, in primary human lymphocytes (PHLCs) treated with HQ. In particular H3K4me3 correlated positively with expression of CRY1 in PHLCs from benzene-exposed workers. These outcomes suggest that H3K4me3 modification might mediate the transcriptional regulation of DDR genes in response to low-dose benzene (or HQ) exposure, which may be related to PARP-1 and γ-H2AX.