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Epigenetics from Oocytes to Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Dagnė Daškevičiūtė, Marta Sanchez-Delgado, David Monk
Histone modifications are key regulatory signals throughout pre-implantation embryo development that influence transcription factor (TF) interactions with the underlying chromatin. Until relatively recently, our knowledge of histone modification reprogramming was restricted to observations from immunofluorescent staining with no precise genome localization known.39 However, the development of low-input and high-resolution techniques for mapping histone modifications, such as ChIP-seq, CUT&Run, and CUT&Tag40–42 have allowed for histone modification demarcation of distinct genomic features in pre-implantation embryos43–46 (Figure 9.1). For example, H3K4me3 is a hallmark of active promoters; H3K27me3 is a repressive histone mark that preferentially occupies promoters of developmental genes, whilst H3K27ac is widely used to differentiate active enhancers (reviewed in 7). Interestingly, in mice several histone modifications show noncanonical distributions and functions in oocytes and early pre-implantation embryos, including H3K4me3 and H3K27me3 which display widespread domains rather than distinct peaks of enrichment, which are briefly inherited and regulate zygotic expression.40,45,46
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.
A patent review of EZH2 inhibitors from 2017 and beyond
Published in Expert Opinion on Therapeutic Patents, 2023
Guoquan Wan, Huan Feng, Chang Su, Yongxia Zhu, Lidan Zhang, Qiangsheng Zhang, Luoting Yu
EZH2-based dual inhibitors can enhance the therapeutic efficacy of EZH2 inhibitors in solid tumors. The EZH2/PARP dual inhibitor showed good inhibitory activity against two TBNC cell lines with wild-type BRCA. In addition, the combination strategy of EZH2 inhibitors can greatly expand their indications, which is also of concern. Combination approaches of EZH2i and other drugs have been reported in multiple literature, including EZH2i + BCL2i, EZH2i + BCL6i, EZH2i+ PARPi, EZH2i + DNMTi, EZH2i + PI3Ki, EZH2i + BRD4i + MAPKi, etc. More importantly, several clinical trials related to the combination of EZH2i are being carried out, such as EZH2i + PD-1 antibodies (NCT02220842), EZH2i + CTLA-4 antibodies (NCT03525795) and EZH2i + ARi (NCT03480646) [76]. One of the most representative examples was the discovery by Geng et al in 2018 of the reason why EZH2 inhibitors such as EPZ-6438/GSK126 were not effective in the treatment of solid tumors [61]. The data showed that the increase in H3K27ac was associated with the response to EZH2i. Blockage of H3K27ac signal context-dependently activates the MAPK pathway. The EZH2i + BRD4i + MAPKi triple-combination therapy significantly suppressed tumor growth.
Upregulation of OATP1A2 in human oesophageal squamous cell carcinoma cells via the HDAC6-GCN5/PCAF-H3K9Ac axis
Published in Xenobiotica, 2021
Xiaoli Zheng, Jian V. Zhang, Yanfeng Bai, Jiaqi Wang, Mingfeng Jiang, Su Zeng, Lvhua Wang
Histone acetylation sites such as H3K18ac, H3K27ac and H3K9Ac are associated with high gene expression. ChIP-qPCR was used to quantify active histone acetylation sites at the OATP1A2 promoter. We initially observed that OATP1A2 transcription was markedly increased in the three selected pairs of ESCC tissues (Figure 4(A)). By employing ChIP-qPCR analysis, highly enriched H3K9Ac was observed around the transcription start site (TSS) of OATP1A2 in SAHA-treated ESCC cells (Figure 4(B, C)). ChIP assays in the normal oesophagus and paired ESCC tissues further revealed that H3K9Ac was enriched at the OATP1A2 promoter of tumour tissues in vivo (Figure 4(D)). It was suggested that gene-specific enrichment of H3K9Ac occurs at the OATP1A2 promoter when OATP1A2 is upregulated in ESCC.
Ficolin-1 and ficolin-3 polymorphisms and susceptibility to rheumatoid arthritis
Published in Autoimmunity, 2020
Cristhine Pieczarka, Fabiana Antunes Andrade, Sandra Jeremias Catarino, Kárita Cláudia Freitas Lidani, Lorena Bavia, Regina Tizzot, Thelma Skare, Iara Jose de Messias-Reason
We also evaluated through gene expression databases the possible influence of such polymorphisms in the FCN1 mRNA expression. All except one (c.-399G>A) FCN1 variants were related to gene expression in many tissue samples, such as whole blood, breast, skeletal muscle, skin, and adipose subcutaneous tissue. The c.-542GG and c.-144CC genotypes associated with RA, were related to lower FCN1 expression (p < .00001 in each tissue) (Table 2). According to the UCSC, c.-542G>A and c.-144C>A are in a position enriched for typical histone modification known to be associated with active regulatory elements (H3K27ac—H3 acetylated at lysine 27) in haematopoietic cell lines. In addition, c.-542G>A and c.-144C>A are in a binding site to POLR2A (RNA Polymerase II Subunit A), MYC (cell-avian myelocytomatosis) and MAX (MYC-associated protein X). All these transcription factors are considered the most evident regulatory proteins that may bind to this region, as seen by chromatin immunoprecipitation assay (https://genome.ucsc.edu/).