- Epigenetics can be defined as “a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence.
- Practically, the term "Epigenetics" refers to DNA and chromatin modifications that persist during cell division
- Epigenetic regulation is essential for cell fate decisions and cellular functions.
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cis-elements are DNA sequences that are located on the same strand of DNA as a gene, and they regulate the transcription of that gene. Cis-elements can be located upstream (5') or downstream (3') of the gene, or even within the gene itself.
Cis-regulatory elements, such as promoters, enhancers, and silencers, are regions of non-coding DNA, which regulate the transcription of nearby genes
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Trans-factors are molecules that bind to cis-elements and regulate gene expression. These molecules can include transcription factors, RNA-binding proteins, and other regulatory proteins. Trans-factors can bind to cis-elements located near the gene, or they can bind to cis-elements located far away on the same chromosome, or even on a different chromosome.
trans-regulatory factors regulate (or modify) the expression of distant genes by combining with their target sequences
Polycomb-group proteins (PcG proteins) are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place.
- The mammalian PRC1 core complexes are very similar to Drosophila.
https://link.springer.com/article/10.1186/s13072-020-00369-1
Polycomb repressive complex 2 (PRC2) is a chromatin-modifying enzyme that catalyses the methylation of histone H3 at lysine 27 (H3K27me1/2/3). This complex maintains gene transcriptional repression.
- Multiple PcG proteins can coordinate and assemble into large multimeric protein complexes with distinct functions.
- In mammals, they form two major complexes, namely, Polycomb Repressive Complex 1 (PRC1) and 2 (PRC2).
https://link.springer.com/article/10.1186/s13072-020-00369-1
Polycomb group (PcG) proteins are epigenetic regulators that function by modifying chromatin. The PcG proteins were originally found in Drosophila melanogaster over 70 years ago. PcGs were determined as negative regulators of homeotic (Hox) genes. Since then, an increasing number of PcG proteins have been identified, from yeast, fungi, plants to animals.
https://link.springer.com/article/10.1186/s13072-020-00369-1
- PRC1 catalyses the monoubiquitylation of histone H2A at lysine 119 (H2AK119ub1).
- It is required for the Polycomb-mediated transcriptional repression
https://link.springer.com/article/10.1186/s13072-020-00369-1
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PRC2 catalyses the methylation of histone H3 at lysine 27 (H3K27me1/2/3). H3K27me2/3 are closely related to silent genomic regions
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Mammalian PRC2 contains three core subunits: EZH1/2, EED and SUZ12
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EZH2 associates with EED and EZHIP. The catalytic activity of PRC2 relies on the SET domain of EZH1/2. But EZH1/2 exhibits no detectable histone methyltransferase (HMTase) activity by itself.
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EED binds to H3K27me3 and stimulates the enzymatic activity of PRC2
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SUZ12 functions as a structural platform that stabilizes the PRC2 holoenzyme AND defines distinct PRC2 subcomplexes by associating with RBBP4/7 and other sub-stoichiometric partners
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Two alternative subtypes of PRC2, namely, PRC2.1 and PRC2.2
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PRC2.1 includes one of the Polycomb-like (PCL) proteins–PHF1, MTF2 or PHF19, and either PALI1/2 or EPOP
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PRC2.2 contains AEBP2 and JARID2
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tissue-specific PRC2 component EZHIP, which can associate with EZH2
- early embryonic lethality of mice lacking the PRC2 core subunits
- In humans, germline monoallelic mutations in PRC2 subunits may cause multisystem genetic disorders, such as overgrowth-intellectual disability (OGID) syndromes
- mutation or dysregulation of PRC2 subunits is frequently observed in multiple cancers and diseases: glioblastoma multiforme (GBM), melanoma, diffuse large B-cell lymphoma (DLBCL), T-cell acute lymphoblastic leukaemia (T-ALL)
https://link.springer.com/article/10.1186/s13072-020-00369-1
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Polycomb response elements (PREs) are regulatory sites that mediate the silencing of homeotic and other genes.
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The most common feature of the mammalian PRC2-binding region is the presence of CpG islands (CGIs). => CpG islands are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide, connected by a phosphate group. These regions are often found near gene promoters and are typically unmethylated, which allows for gene expression. The presence or absence of CpG methylation can affect gene regulation and is associated with various diseases such as cancer.
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In mouse embryonic stem cells (mESCs) and human embryonic stem cells (hESCs), more than 90% of the PRC2-enriched regions closely correspond to CGIs or CpG-rich regions, which lack DNA methylation and are adjacent to the transcription start site (TSS) of the promoter in the silenced genes
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several PRC2 facultative subunits, such as JARID2 and PCLs, also exhibit binding preferences for CpG-rich sequences
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Most mammalian gene promoters contain CGIs, but only a minority are PRC2-positive.
https://link.springer.com/article/10.1186/s13072-020-00369-1
- pharmacological intervention: small-molecule inhibitors targeting EZH2 in cancer therapy
knockdown
knockout
siRNA/shRNA
CRISPR