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Epigenetic control of cell fate and behavior
Published in David M. Gardiner, Regenerative Engineering and Developmental Biology, 2017
Besides covalent modifications of nucleic acids, DNA-associated proteins can also be modified to affect gene expression. Histone proteins aid in the compaction and structure of chromatin, but they can be modified through various mechanisms in order to influence their level of association with DNA and their ability to interact with transcription factors. Mechanisms of histone modification include phosphorylation, ADP-ribosylation, ubiquitylation, and sumoylation, but the most characterized mechanisms are methylation and acetylation (Jenuwein and Allis 2001). Methylation of histones occurs primarily on lysine and arginine residues and can result in either gene silencing or activation, depending on the residue modified. Figure 18.4 depicts DNA associated with histones containing various modifications. For example, trimethylation of histone 3 at lysine position 4 (H3K4me3) is found to be enriched at promoters of transcriptionally active genes. This modification recruits chromatin-remodeling factors and positively regulating transcription factors resulting in gene expression (Tomazou and Meissner 2010). On the other hand, trimethylation of histone 3 at lysine position 27 (H3K27me3) is tightly associated with inactive gene promoters (Meissner 2010). Generally speaking, H3K4 trimethylation and H3K27 trimethylation are opposed to one another; however, several genes have been discovered to have both modifications, also known as marks, at their promoters. This results in a sort of primed state of bivalency, in which a gene is silenced but it carries marks for activation. Presumably, the removal of the repressive mark would then allow the already-present active mark to induce gene expression more rapidly (Bernstein et al. 2006).
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.
Genetic polymorphisms of PPAR genes and human cancers: evidence for gene–environment interactions
Published in Journal of Environmental Science and Health, Part C, 2019
In summary, although the PPAR-β/δ-null mouse model showed strong in vivo evidence of a role of PPAR receptors in development and cell proliferation,44 however, so far, studies that convincingly proved a clear association between exposure to PPAR ligands and carcinogenicity are still inconclusive, particularly in humans. It is important to consider that a ligand that activates a PPAR, may at the same time cause toxicity through other mechanisms of action. Ligand-induced toxicity may take place by receptor-independent events, or by both PPAR-dependent and PPAR-independent mechanisms.45 Additionally, if/when a PPAR mediates an adverse effect, genetic polymorphisms of that PPAR need to be examined as they may be significant effect modifiers. Further, like most transcription factors, PPARs may be influenced by epigenetic regulators, which may modify ligand-mediated transcription and gene expression pathways. Epigenetic mechanisms, such as histone acetylation, DNA methylation, and miRNAs, may promote or inhibit the transcription of various PPARs by governing their mRNA translation or breakdown. Recently, a zinc-finger protein was identified among a group of unidentified transcription factors bound to the PPAR-γ gene non-methylated promoter.46 Following an unknown trigger, the promoter gets hypermethylated, enriched in H3K9me2 & 3, and H3K27me3, then followed by binding a repressive complex, including DNMT2b, HDAC1, EZH2, and other components, ultimately resulting in repression of transcription. In addition, posttranslational modifications (such as phosphorylation and ubiquitination), interactions with coactivators -such as PPARGCA, CBP-p300, and SCRC1- and corepressors -such as RIP140α, SMRTα- may also affect the transcriptional activity and stability of PPARs.47 So far, very few studies have examined the contribution of these mechanisms to PPAR-mediated cancer risk.