Histone H3

By Emily Cartwright, PhD

Epigenetic mechanisms have been implicated in many physiological and pathophysiological processes. Among these, histone modifications including methylation, phosphorylation, acetylation and ubiquitination, significantly modify gene expression.

Epigenetics is the process of heritable change in gene activity despite alteration of the hosts DNA sequence, essentially causing a change in a phenotype without a change in the genotype of a host. To change the gene sequence without interfering with the DNA is accomplished by histone and DNA methylation.  Gene silencing in DNA methylation is carried out by DNA methyltransferases 1, 2 and 3a/b (DNMT1, DNMT2, DNMT3A/B). On a broad level, DNMT’s methylate the fifth carbon of cytosine residues in DNA within CG dinucleotides.

Epigenetics is the study of heritable change in gene activity despite alteration of the hosts DNA sequence.  Change in gene activity done independently of the DNA sequence is achieved by way of histone and DNA methylation.  Gene silencing in DNA methylation is carried out by DNA methyltransferases 1, 2 and 3a/b (DNMT1, DNMT2, DNMT3A/B). On a broad level, DNMTs methylate the fifth carbon of cytosine residues in DNA within CG dinucleotides.

EZH1 is part of the Polycomb-group family of proteins, which are responsible for remodeling chromatin in genes and modulating epigenetic silencing during development.  Specifically, EZHI is a component of PRC2, or polycomb repressive complex-2.  PRC2 interacts and modifies the histone “H3”, and is critical in maintaining gene repression.

RNA polymerase II is a large 12-subunit complex that synthesizes all mRNAs and several non-coding RNAs in eukaryotic cells. It is a DNA-dependent RNA polymerase enzyme that catalyzes transcription of DNA into RNA based on the four ribonucleoside triphosphate building blocks. RNA polymerase II is regulated through DNA-binding transcriptional regulators in both gene and cell type-specific manners.

Eukaryotic chromosomes are formed through the highly organized and structural wrapping of DNA genetic material around histone proteins into the classic "bead on a string" globular structure of nucleosomes. The histone family consists of five family members - histone H1, H2A, H2B, H3, and H4.

Enhancer of Zeste homolog 2 (EZH2) is the methyltransferase enzyme responsible for trimethylating lysine 27 on histone H3 to produce H3K27Me3. EZH2 is a polycomb group protein that is an essential epigenetic regulator that is often found deregulated in a wide variety of malignant cancer types.

Epigenetic mechanisms allow distinction between the active and inactive compartments of the genome, allowing proper cell lineage and embryogenesis.

Discovery of histone variants using highly specific antibodies has led to the emerging notion that alterations in histone modifications and further changes in chromatin structure are induced by exchange of histone variants. Covalent histone modifications and the incorporation of histone variants bring about changes in chromatin structure that in turn alter the gene expression.