The non-genetic cellular memory, which records developmental and environmental cues is the basis of epigenetics. One of the most important epigenetic processes is to regulate the interactions between histones and DNA. The key players in this phenomenon are the "readers", the "writers" and the "erasers". These epigenome constituents play a critical part in establishing functional chromatin states. However, epigenetic signatures in the form of post-translational modifications on histones are not permanent. The epigenetic marks are removed by a set of enzymes known as erasers or eraser enzymes. These enzymes are essential for the epigenetic reprogramming events that are required during developmental stages. At the cellular level, the activity of erasers is important for transition from one cell cycle phase to another. There are multiple categories of epigenetic erasers that target histones. BioVision's epigenetic eraser enzymes portfolio includes histone deacetylases (HDACs), histone lysine/arginine demethylases (HDMs), histone deubiquitinases, protein tyrosine phosphatases and Sirtuins (SIRTs).
Histone acetylation marks are removed by 'histone deacetylases' (HDACs). They contain a 'histone deacetylase' catalytic domain that mediates this function. Eighteen HDACs are known in humans that are classified into 4 classes based on homology: Class I, IIa, IIb, III and IV and each of these classes contains a specific set of HDACs. The mechanism of catalysis is same for Class I, II and IV wherein a metal ion (Zn/Fe) present at the active site makes a coordinate bond with the oxygen of the carbonyl group and activates a water molecule with the help of nearby histidine/aspartic acid for a nucleophilic attack that further causes removal of the acetyl group. Sirtuins have a rather different mechanism wherein they first bind the acetylated substrate followed by NAD+. NAD+ is then converted to nicotinamide after attack of carbonyl oxygen. The intermediate formed is alpha-1'-O-alkylamidate that finally deacetylates lysine and gives 2'-O-acetyl-ADP-ribose as the product. Apart from histones, HDACs have several non-histone targets as well. Biovision's HDAC portfolio includes several assay kits, enzymes, inhibitors and antibodies as listed below.
Histone methylation marks convey important information in terms of gene regulation. But these marks need to be exchanged time and again in order to switch gene expression as and when required. Two major types of demethylase are known: 1) Lysine-specific demethylase (LSD1/KDM1): They contain an amine oxidase (AO) catalytic domain that mediates oxidative demethylation of methylated lysine residues by reducing FAD molecules; 2) Jumonji histone demethylases: They contain the catalytic JmJC domain and may or may not contain other associated domains like JmJN, ARID, PHD, Tudor etc. Based on domain architecture and homology, they are divided into 7 groups: JHDM1, JHDM2, JHDM3/JMJD2, JARID, JMJC domain only, PHF2/PHF8 and UTX/UTY. Histone demethylases have important role in various cellular processes like cell cycle progression, transcriptional regulation of hox genes, nuclear hormone mediated and NF-kB signaling, p53 regulation, unperturbed mitosis, fetoplacental development, regulation of DNA replication, control of rRNA expression, DNA repair processes etc. Biovision's HDM portfolio consists of inhibitors, enzymes and antibodies/blocking peptides.
Histone deubiquitinases cleave the Ubiquitin moieties attached to the core histones. These are divided into 5 major classes: I to V. Classes I to IV are cysteine peptidases and V is a zinc metalloisopeptidase. Deubiquitinases significantly affect transcriptional regulation, DNA damage response, cytokinesis, telomere maintenance. We have many antibodies, enzymes and inhibitors in this portfolio.
Proteins that catalyze the removal of phosphate groups from the target proteins are called phosphatases. They are functionally of 2 types: one that dephosphorylate serine/threonine residues; others that dephosphorylate tyrosine residues. Protein Ser/Thr phosphatases PP1, PP2A and PP4, amongst others, have been reported to dephosphorylate histone proteins. Histone dephosphorylases play a significant role in DNA damage repair pathways by dephosphorylating histone gamma-H2AX (phosphorylated form of H2AX) after successful DNA damage response has been elicited. This becomes part of cellular homeostasis. They are also supposedly involved in microtubule organization. This category of BioVision products includes assay kits, proteins, inhibitors and antibodies.
In summary, the eraser enzymes are essential for the epigenetic reprogramming events that are required during developmental stages. Certain erasers like HDACs exhibit tremendous potential as targets for cancer therapeutics. Inhibitors designed against HDACs have now entered drug trials and may emerge as potent drugs for cancer treatment in future.