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Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.
Polycomb-group proteins are a family of protein complexes first discovered in fruit flies that can remodel chromatin such that epigenetic silencing of genes takes place. Polycomb-group proteins are well known for silencing Hox genes through modulation of chromatin structure during embryonic development in fruit flies. They derive their name from the fact that the first sign of a decrease in PcG function is often a homeotic transformation of posterior legs towards anterior legs, which have a characteristic comb-like set of bristles.
Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.
Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the HDAC2 gene. It belongs to the histone deacetylase class of enzymes responsible for the removal of acetyl groups from lysine residues at the N-terminal region of the core histones. As such, it plays an important role in gene expression by facilitating the formation of transcription repressor complexes and for this reason is often considered an important target for cancer therapy.
Enhancer of zeste homolog 2 (EZH2) is a histone-lysine N-methyltransferase enzyme encoded by EZH2 gene, that participates in histone methylation and, ultimately, transcriptional repression. EZH2 catalyzes the addition of methyl groups to histone H3 at lysine 27, by using the cofactor S-adenosyl-L-methionine. Methylation activity of EZH2 facilitates heterochromatin formation thereby silences gene function. Remodeling of chromosomal heterochromatin by EZH2 is also required during cell mitosis.
Histone-lysine N-methyltransferase SUV39H1 is an enzyme that in humans is encoded by the SUV39H1 gene.
Polycomb protein SUZ12 is a protein that in humans is encoded by the SUZ12 gene.
Polycomb protein EED is a protein that in humans is encoded by the EED gene.
Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase. It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A, KMT2B, KMT2C, KMT2F, and KMT2G.
Histone-lysine N-methyltransferase EZH1 is an enzyme that in humans is encoded by the EZH1 gene.
Trithorax-group proteins (TrxG) are a heterogeneous collection of proteins whose main action is to maintain gene expression. They can be categorized into three general classes based on molecular function:
- histone-modifying TrxG proteins
- chromatin-remodeling TrxG proteins
- DNA-binding TrxG proteins,
In molecular biology, a Tudor domain is a conserved protein structural domain originally identified in the Tudor protein encoded in Drosophila. The Tudor gene was found in a Drosophila screen for maternal factors that regulate embryonic development or fertility. Mutations here are lethal for offspring, inspiring the name Tudor, as a reference to the Tudor King Henry VIII and the several miscarriages experienced by his wives.
Adipocyte Enhancer-Binding Protein is a zinc finger protein that in humans is encoded by the evolutionarily well-conserved gene AEBP2. It was initially identified due to its binding capability to the promoter of the adipocyte P2 gene, and was therefore named Adipocyte Enhancer Binding Protein 2. AEBP2 is a potential targeting protein for the mammalian Polycomb Repression Complex 2 (PRC2).
Plants depend on epigenetic processes for proper function. Epigenetics is defined as "the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence". The area of study examines protein interactions with DNA and its associated components, including histones and various other modifications such as methylation, which alter the rate or target of transcription. Epi-alleles and epi-mutants, much like their genetic counterparts, describe changes in phenotypes due to epigenetic mechanisms. Epigenetics in plants has attracted scientific enthusiasm because of its importance in agriculture.
Epigenetics of human development is the study of how epigenetics effects human development.
The Ezh2 gene is a component of polycomb repressive complex 2 (PRC2). This histone methyltransferase performs its biological activity by catalyzing the trimethylation of histone 3 lysine 27 (H3K27me3). The biological function of this gene allows for it to transcriptionally repress the target, Hox, inhibitor genes of osteochodrogenesis. Ezh2 is crucial for epigenetic regulation of specific patterning during osteochondrogenesis, or bone and cartilage development, of the craniofacial skeletal elements. By repressing inhibitors, Ezh2 promotes bone and cartilage formation in facial skeletal features arising from the neural crest. Above average Ezh2 expression has become a biological marker for the most aggressive form for breast cancer known as Inflammatory Breast Cancer (IBC). But in 2013, a study performed by Zhaomei Mu and his associates concluded that the knockdown gene for Ezh2 inhibited both the migration and invasion of IBC cells. Also in vivo, its knockdown gene suppressed tumor growth, most likely by the presence of fewer blood vessels, or reduced angiogenesis, in the Ezh2 knockdown tumor versus Ezh2 tumors.
H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.
Thomas Jenuwein is a German scientist working in the fields of epigenetics, chromatin biology, gene regulation and genome function.
Yi Zhang is a Chinese-American biochemist who specializes in the fields of epigenetics, chromatin, and developmental reprogramming. He is a Fred Rosen Professor of Pediatrics and Professor of Genetics at Harvard Medical School, a Senior Investigator of Program in Cellular and Molecular Medicine at Boston Children's Hospital, and an Investigator of the Howard Hughes Medical Institute. He is also an Associate Member of the Harvard Stem Cell Institute, as well as the Broad Institute of MIT and Harvard. He is best known for his discovery of several classes of epigenetic enzymes and the identification of epigenetic barriers of SCNT cloning.
H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.
References
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- 1 2 3 Chase A, Cross NC (May 2011). "Aberrations of EZH2 in cancer". Clinical Cancer Research. 17 (9): 2613–2618. doi: 10.1158/1078-0432.CCR-10-2156 . PMID 21367748.
- ↑ Geisler, Sarah J.; Paro, Renato (2015-09-01). "Trithorax and Polycomb group-dependent regulation: a tale of opposing activities". Development. 142 (17): 2876–2887. doi: 10.1242/dev.120030 . ISSN 0950-1991. PMID 26329598.
- ↑ Heurtier, V., Owens, N., Gonzalez, I. et al. The molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells. Nat Commun 10, 1109 (2019). https://doi.org/10.1038/s41467-019-09041-z
- 1 2 3 Veneti Z, Gkouskou KK, Eliopoulos AG (July 2017). "Polycomb Repressor Complex 2 in Genomic Instability and Cancer". Int J Mol Sci. 18 (8): 1657. doi: 10.3390/ijms18081657 . PMC 5578047 . PMID 28758948.
- 1 2 3 4 Koehler, Claudia; Hennig, Lars (2010). "Regulation of cell identity by plant Polycomb and trithorax group proteins". Current Opinion in Genetics & Development. 20 (5): 541–547. doi:10.1016/j.gde.2010.04.015. PMID 20684877.