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Epigenetics of exercise
Published in Adam P. Sharples, James P. Morton, Henning Wackerhage, Molecular Exercise Physiology, 2022
Daniel C. Turner, Robert A. Seaborne, Adam P. Sharples
When examining further, authors also reported a significant increase in tri-methylation of H3K27 in absolute terms, and relative to levels of H3. They also reported an increase in acetylation of H3 and mono methylation of H3K4, when relativised to levels of total H3 (95), where previous in vitro work reported H3K27me3 and H3K4me1 to be negatively and positively correlated with gene transcription, respectively, in a wider range of cell types (24). In a muscle-specific context, both these marks seem to be highly conserved to the myogenic basic helix loop helix (bHLH) transcription factor, MyoD, in both myoblasts and myotubes, leading to muscle-specific gene transcription (97) (MyoD and its role in myogenesis/satellite cells with exercise are covered in Chapter 13). Despite these interesting results, very few other studies have characterised the regulation of histone modifications following RE training; thus, it remains an under-developed area of molecular exercise physiology research. It is, however, a tantalising avenue of research and is surely poised to see a flurry of exciting, explorative, and illuminating work in the near future.
Role of Histone Methyltransferase in Breast Cancer
Published in Meenu Gupta, Rachna Jain, Arun Solanki, Fadi Al-Turjman, Cancer Prediction for Industrial IoT 4.0: A Machine Learning Perspective, 2021
Surekha Manhas, Zaved Ahmed Khan
Regulation of gene expressions in eukaryotic organisms is regulated synergistically through different transcriptional factors, including chromatin remodelers, specific histone variants, transcriptional machinery, and histone modifications but not limited to these factors. Active domains of chromatin are usually characterized by apparent series associated with histone marks. H3K4me1 and H3K27ac are connected with specific active enhancers [10]. The H3K4me3 level is high at promoter sequences of active genes, and acetylation of H4 and H3 are within specific promoters of active genes [11–13]. Active gene bodies are mostly enriched in H4 and H3 acetylation [14], H2BK120u1 [15,16] and H3K79me3 acetylation [7], and H3K36me3 acetylation increasing toward the 30 end [17]. These different histone marks might regulate transcriptional regulation of genes by generating open chromatin structures along with effector recruitment that helps to mediate competent state transcriptionally. Although the varied function of various active modifications of histone proteins is not fully recognizable and understandable, there is still an abundance of data available in the literature that shows that deposition of these histone marks is necessary for the appropriate gene expression regulation mechanism. There are various distinct positive crosstalk mechanisms found between several distinct modifications of histone proteins, which play a crucial role in maintenance and recruitment at the site of active genes through histone modifications.
Predictive Modeling with Supervised Machine Learning
Published in Altuna Akalin, Computational Genomics with R, 2020
Apart from prediction of an outcome, machine learning can be used to understand which predictor variables are the most important for prediction performance. This often gives insights into the biology as well. Many machine learning algorithms have either built-in variable importance assessment or can be wrapped around a model-agnostic variable importance method. For example, we may want to find which epigenetic modifications are most important for gene expression prediction. Although decades of molecular biology gives a pretty good idea for this, we could arrive at similar conclusions by building a machine learning model to predict gene expression using histone modifications H3K27ac, H3K27me, H3K4me1, H3K4me3, and DNA methylation. We can then check which of these are most important for gene expression prediction using variable importance metrics.
Dysregulated translational factors and epigenetic regulations orchestrate in B cells contributing to autoimmune diseases
Published in International Reviews of Immunology, 2023
Ming Yang, Ping Yi, Jiao Jiang, Ming Zhao, Haijing Wu, Qianjin Lu
Ezh2 in ASCs downregulates the expression of B cell-specific genes gaining H3K27me3, such as Blimp1 repressed genes, and influences ASC metabolism, contributing to TI ASC differentiation and antibody production function [100]. Lysine-specific demethylase 1 (LSD1) demethylates active histone modification H3K4me1 to decommission BN cell active enhancers and cooperates with Blimp1 to repress Blimp1-repressed genes, thus regulating the differentiation of PB and plasma cells, as well as TI B cell proliferation [101]. Similarly, H3K4 methyltransferase KMT2D promotes CSR, terminal differentiation of GC B cells, normal B cell response and antibody production [102]. Further, KRAB-associated protein 1 (KAP1), a cofactor of Krüppel-associated box zinc finger proteins (KRAB-ZFPs), induces heterochromatin modifications H3K9me3 and histone deacetylation to silence tumor suppression gene PTEN, an antagonist of PI3K that mediates BCR signaling, and genes coding DNA damage response factors, and the number of mature B cells and antibody level were decreased in Kap1 knockout mice [103]. MiR17-92 targets PTEN and Bim (a member of Bcl2 family) to predispose humans to autoimmunity [104]. Histone deacetylase inhibitors (HDIs) silence AID, Blimp1 and XBP1 expression by upregulating miRNAs targeting gene transcription, thus inhibiting CSR, SHM and plasma cell differentiation [105]. The epigenetic alterations involved in B cell maturation and differentiation of several autoimmune diseases are shown in Figure 3.
Discovery of novel sulphonamide hybrids that inhibit LSD1 against bladder cancer cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Jia Liu, Xingwang Zhu, Liu Yu, Minghuan Mao
Bladder cancer is the most frequently diagnosed malignancy in the urinary system and has the high morbidity and mortality rates1. Chemotherapy plays an important role in the treatment of bladder cancer and it is urgent to develop potent anti-bladder cancer drugs2,3. Histone lysine-specific demethylase 1 (LSD1) could catalyse the demethylation of mono and dimethylated H3K4me1/2 or H3K9me1/2 and demethylate many other nonhistone substrates4. LSD1 is aberrantly expressed in many malignant tumours such as prostate, ovarian, gastric, liver, breast, lung, bladder, neuroblastoma, and blood cancers5. The inhibition of LSD1 could prevent tumour cell proliferation, stimulate antitumor immunity, and enhance antitumor efficacy of immune checkpoint blockade6. Therefore, LSD1 has been considered as a potential cancer therapeutic target to discover novel anti-bladder cancer agents7–9. LSD1 and MAO-A/-B were belonged to the monoamine oxidase family, and MAO-A/-B shared the similar enzymatic mechanisms and the same cofactor of LSD1 in the cleavage of the inactivated carbon–nitrogen bonds from their substrates10. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient selectivity towards LSD111.
Application of NanoString technologies in companion diagnostic development
Published in Expert Review of Molecular Diagnostics, 2019
Jennifer Mary Eastel, Ka Wai Lam, Nga Lam Lee, Wing Yan Lok, Andy Hin Fung Tsang, Xiao Meng Pei, Amanda Kit Ching Chan, William Chi Shing Cho, Sze Chuen Cesar Wong
ChIP-string was reported to be applied in systematic analysis to reveal any epigenomic changes in melanoma progression. A strategy using a ChIP-string assay with 96 designed test probes was used to evaluate the key epigenetic features observed in different cell lines. Six selected histone regions were selected for investigation. They were H2BK5ac, H4K5ac, H3K27ac, H3K4me1, H3K4me3, and H3K27me3, which represented promoters, enhancers or polycomb-repressed regions. Results revealed that the loss of histone acetylations and H3K4me3 on regulatory regions were associated with melanoma development. Upon treatment with histone deacetylase inhibitors, restoration of acetylation on deacetylated loci suppressed the aggressive proliferation of tumorigenic cells [29]. There was also a good correlation between the signal generated from ChIP-string and ChIP-sequencing.