- Histone acetyltransferases (HATs) are enzymes that catalyze the transfer of acetyl groups from acetyl-CoA to the ε-amino group of lysine residues on histone proteins, primarily in the N-terminal tails of histones H3 and H4. This post-translational modification, known as histone acetylation, plays a pivotal role in the regulation of chromatin structure and gene expression.
- By neutralizing the positive charge of lysine residues, acetylation reduces the interaction between histones and the negatively charged DNA, leading to a more relaxed, transcriptionally permissive chromatin conformation.
- HATs are broadly classified into two categories: type A HATs, which function in the nucleus and are involved in transcriptional regulation, and type B HATs, which operate in the cytoplasm and acetylate newly synthesized histones before their incorporation into chromatin. Type A HATs can be further divided into several families based on structural and functional characteristics, including the GNAT (Gcn5-related N-acetyltransferase) family, the MYST (Moz, Ybf2/Sas3, Sas2, Tip60) family, and the p300/CBP (CREB-binding protein) family. Each of these families targets specific histone residues and is often recruited to chromatin by transcription factors or chromatin remodelers.
- The primary function of HATs in gene regulation lies in their ability to facilitate transcriptional activation. Acetylated histones provide a more open chromatin environment that enables the binding of transcription factors, RNA polymerase II, and other components of the transcriptional machinery. In addition, acetyl-lysine residues serve as docking sites for bromodomain-containing proteins, which further enhance transcriptional activation by recruiting coactivators and chromatin remodeling complexes. HATs can also acetylate non-histone proteins, such as transcription factors and nuclear receptors, modulating their stability, localization, or DNA-binding affinity.
- Beyond transcriptional control, HATs participate in various cellular processes including DNA repair, replication, cell cycle progression, and differentiation. For example, Tip60, a member of the MYST family, plays a crucial role in the DNA damage response by acetylating histone H4 and the tumor suppressor p53. Gcn5 is important for cell growth and metabolic regulation, while CBP/p300 are essential coactivators for many signal transduction pathways and are frequently involved in development and stem cell biology.
- Dysregulation of HAT activity has been linked to numerous human diseases, particularly cancer. Overexpression or mutation of certain HATs can lead to aberrant acetylation patterns, resulting in inappropriate gene activation or silencing. For instance, mutations in CREBBP or EP300 (encoding CBP and p300, respectively) are common in hematologic malignancies and solid tumors, where they may disrupt tumor suppressor gene expression or impair differentiation. Additionally, imbalanced HAT activity has been implicated in neurodevelopmental disorders such as Rubinstein-Taybi syndrome, which is caused by mutations in the CBP gene.
