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Epigenetic control of cell fate and behavior
Published in David M. Gardiner, Regenerative Engineering and Developmental Biology, 2017
Histone-modifying enzyme activity also becomes altered under, or leads to, cancerous conditions. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex, has been observed to be overexpressed in cancers such as prostate cancer, ovarian cancer, brain cancer, and melanoma, leading to increased levels of the repressive histone 3 lysine 27 trimethylation mark (Yamaguchi and Hung 2014). The SWI/SNF chromatin-remodeling complex typically plays a role of tumor suppressor in normal cells, but its function is inactivated within many cancer types. It functions through somewhat unknown mechanisms but has been determined to shift the position of nucleosomes within a region of DNA (Whitehouse et al. 1999). Approximately 20% of cancers contain mutations in at least one subunit of the SWI/SNF complex, highlighting the importance of epigenetic modifiers in controlling cellular proliferation and differentiation. Overall, the most common aberrant histone modifications described in cancerous states are the methylation of lysine 4, 9, and 27 on histone 3 and the deacetylation of lysine 16.
Genetic and Epigenetic Considerations in iPSC Technology
Published in Deepak A. Lamba, Patient-Specific Stem Cells, 2017
Two main families of PRC, PRC1 and PRC2, are related to H3K27me3-related gene silencing (102). PRC1 includes chromobox proteins (Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8), ring finger proteins (Ring1 and Ring1b), B lymphoma Mo-MLV insertion region 1 (Bmi1), and polycomb group ring finger 2. Cbx proteins bind to H3K27me3, and ring proteins and Bmi1 are required for E3 ubiquitination of histone H2A lysine 119 (H2AK119ub), which retains RNA polymerase II in promoter (103). PRC2 is the most prevalent H3K27me3 writer, and its core components are Ezh2, embryonic ectoderm development (Eed), suppressor of zeste 12 homologue (Suz12), and retinoblastoma-associated proteins 48 (RbAp48 or Rbbp4) (104). Ezh2 has the histone methyltransferase activity, which is stimulated by Eed. Suz12 and RbAp48 are required for DNA and histone binding, respectively. Eed is also important in recruiting PRC1 to H3K27me3-enriched loci by introducing H2AK119ub (105). Eed- (106), Suz12- (107), Ezh2- (108), and Ring1b-deleted ESCs (109) increase the expression of developmental genes with global loss of H3K27me3 and display the aberrant differentiation potential but can maintain pluripotency with serial cell passaging. Interestingly, depleting the expression of components of PRC1 and PRC2 (Suz12, Ezh2, Eed, Ring1, and Bmi1) blocks iPSC reprogramming, indicating that H3K27me3 changes and H3K27me3-mediated regulation during iPSC reprogramming are essential steps for the acquisition of pluripotency and differentiation capacity (47). In contrast, different types of Cbx proteins show unique functions in ESCs (110). Although Cbx6 and Cbx7 are highly expressed in ESCs, only Cbx7 physically interacts with Ring1b and directly targets the developmental genes in ESCs. The deletion of Cbx7 does not affect pluripotency but produces smaller EBs with the downregulation of mesoderm- and endoderm-related genes. Thus, Cbx7 is required for the suppression of developmental genes in pluripotent stage and keeps the balance of commitment toward the germ cell layer. Whereas Cbx7 is downregulated during EB differentiation, the expression of Cbx2 and Cbx4 is increased. Cbx8 is not induced without retinoic acid treatment. In EBs, Ring1b strongly interacts with Cbx2 and Cbx 4, but not with the other Cbx proteins. Although Cbx2- and Cbx4-deleted ESCs also do not alter the pluripotency, the deletion of Cbx2, but not Cbx4, exhibits a smaller size of EB formation. Cbx2 regulates trophoblast, mesoderm, and endoderm markers, but Cbx4 only regulates mesodermal genes. Overall, despite the different molecular mechanism of gene regulation, Cbx proteins are essential for proper differentiation.
Benzo[a]pyrene osteotoxicity and the regulatory roles of genetic and epigenetic factors: A review
Published in Critical Reviews in Environmental Science and Technology, 2022
Jiezhang Mo, Doris Wai-Ting Au, Jiahua Guo, Christoph Winkler, Richard Yuen-Chong Kong, Frauke Seemann
Growing evidence suggests that histone modifications serve a critical role in regulating bone metabolism and osteoporosis (Letarouilly et al., 2019; Liu et al., 2015). For instance, histone deacetylation inhibits osteogenesis and osteoclastogenesis in vitro in bone cells treated with histone deacetylase inhibitors (Boer et al., 2006; Cho et al., 2005). Additionally, methylation and demethylation may function as epigenetic switches for bone MSC lineage fate determination (Hemming et al., 2014). The enhancer of zeste homolog 2 (EZH2), is a histone methyltransferase that is capable of catalyzing the trimethylation of histone H3 on lysine 27 (H3K27me3) on its target genes, thereby inhibiting osteogenesis (Dudakovic et al., 2015). Conversely, lysine demethylase 6 A (KDM6A) promotes osteogenesis (Chen et al., 2011). The phosphorylation of EZH2 inhibits its methyltransferase activity and promotes osteogenesis (Wei et al., 2011).