Reader Domains

Epigenetics is the study of heritable changes in gene expression that occurs without changes in the DNA sequence. It encompasses modifications to the DNA or histone proteins associated with DNA, which regulate gene expression. Examples of post-translational modifications (PTMs) to histones include methylation, acetylation, ubiquitination, SUMOylation, crotonylation, butyrylation and propionylation of lysine residues; methylation, citrullination and ADP-ribosylation of arginine residues; and phosphorylation and glycosylation of serine and threonine residues. These modifications are added to histones by enzymes called "writers" and removed by enzymes called "erasers". Interpretation of the information conveyed in the epigenetic language or code requires a third class of proteins called epigenetic "readers". These molecules recognize and bind to the PTMs produced by the writers and erasers and effect changes in transcription, often through scaffolding the formation of high order transcriptional complexes. Various domains such as Bromo, Chromo, PHD, Tudor, MBT, BRCT, and PWWP that recognize and bind these histone modifications have been identified.

Methylation and Acetylation are the most common PTM's of histones. Two residues—lysine and arginine—can be methylated, and each has three possible methylation states. Unlike other modifications, methylation does not change the overall charge, although it does alter the hydrophobic character and size of the modified residue. Various protein domains called readers recognize specific PTM's on the histones. The bromodomains target acetylated histones and thereby regulate transcription, repair, replication and chromosome condensation. Chromodomains target methylated lysines on histone 3 (H3) resulting in either activation or silencing of gene expression. PHD domains bind to methylated H3 leading to gene activation. DNA repair is mediated by Tudor domains binding to methylated lysine at position 20 on histone 4 (H4) whereas transcription is mediated by tudor domains binding to methylated lysine at position 4 on H3. The PWWP domain found in DNA methyl transferases binds DNA and methylated histones. The MBT domain binds mono- and di- methylated lysines on H3 and H4 tails thereby regulating transcription. Other methyl lysine readers include ADD (ATRXDNMT3-DNMT3L), ankyrin, bromo-adjacent homology (BAH), chromobarrel, double chromodomain (DCD), tandem Tudor domain (TTD), WD40 and the zinc finger CW (zf-CW). Compared to methylysine readers, there is limited information about methylarginine (MeR) readers. TDRD3 Tudor domain recognizes H3R17me2a and H4R3me2a and facilitates recruitment of this co-transcriptional activator to gene promoters. The ADD domain of the DNMT3a DNA methyltransferase has been shown to interact with H4R3me2s, promoting silencing of the human β-globin locus. The association of the WDR5 WD40 module with H3R2me2s, which is produced by PRMT5 and PRMT7, is key for euchromatin maintenance. All these examples show that recognition of methylated arginines in histone proteins can influence transcription processes.

Lysine can also be acetylated at the -amino group and unlike methylation, acetylation changes the electrostatic properties of histone proteins by neutralizing the charge of lysine. The bromodomain is the most thoroughly studied acetyllysine reader. Bromodomains, found in histone acetyl transferases and other chromatin-associated proteins, are an evolutionarily conserved family of ~110 amino acid modules. The bromodomain and extra-terminal (BET) proteins comprise the ubiquitously expressed BRD2, BRD3 and BRD4. The expression of BRDT is restricted to testes. Binding of BET proteins to specific gene loci recruits protein complexes, including the mediator complex and the super elongation complex (SEC)/pTEFb. These complexes are involved in the initiation and elongation phases of transcription, respectively. BET proteins are important positive regulators of transcription and are predicted to control expression of a variety of mediators of critical cellular processes. Recently, two different inhibitors, I-BET762 and JQ1, have been developed that inhibit the protein-protein interaction between BET proteins and acetylated lysines in histone tails. These inhibitors are currently being tested for a range of hematologic malignancies.

Compared to other post-translational modification of histones, much less is known about histone phosphorylation. Only two readers have been identified for phosphorylated serine (PhS) in histones. The BRCT domain of MDC1 binds to PhS near C-terminus of histone H2AX. PhS is also read by the 14-3-3 family.

Recognition of PTMs by histone readers seems to gain significant attention in chromatin biology. Future studies in this area should provide significant insight into the epigenetic regulatory mechanisms and may lead to the discoveries of new pharmacological targets and biomarkers.

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