A Breakdown of the Different HDAC Classes

Within our cells, the genetic blueprint in DNA is organized by being wrapped around proteins called histones, forming a complex known as chromatin. The accessibility of this DNA for gene activation is regulated by enzymes, including Histone Deacetylases (HDACs). These enzymes function by removing chemical tags, called acetyl groups, from histones. This action causes the chromatin to become more compact, restricting access to the DNA and influencing which genes are turned on or off.

This enzymatic regulation is a dynamic process, and the balance between adding and removing these acetyl tags allows for precise control over gene expression. Given the variety of HDACs, scientists group them into families to better understand their diverse functions.

How Scientists Group HDACs: Understanding the Classes

The classification of the 18 known mammalian HDACs into four main groups is based on several biochemical and evolutionary characteristics. A primary criterion is sequence homology, which is the similarity of their amino acid sequences to enzymes first discovered in yeast. This evolutionary relationship provides a blueprint for understanding their function.

HDACs are also grouped by their structural design and the molecules they require to perform their function. Most of these enzymes, belonging to Classes I, II, and IV, depend on a zinc ion (Zn2+) to remove acetyl groups. In contrast, Class III HDACs operate through a different mechanism that requires nicotinamide adenine dinucleotide (NAD+) as a cofactor.

This difference in cofactor dependency, combined with sequence similarities and their location within the cell, establishes the four distinct categories. This grouping helps researchers predict the functions and regulatory mechanisms of newly studied HDACs based on the class to which they belong.

Class I HDACs: The Nuclear Workhorses

Class I HDACs, which include HDAC1, HDAC2, HDAC3, and HDAC8, are defined by their primary residence within the cell’s nucleus. These enzymes are found in a wide variety of tissues, reflecting their involvement in processes common to most cell types. A defining feature of Class I HDACs is that they do not operate in isolation.

Instead, they are components of large, multi-protein assemblies that act as gene repressors. By being part of these larger machines, HDAC1, HDAC2, and HDAC3 are recruited to specific locations on the genome to control gene expression. Their role within these complexes makes them regulators of cell proliferation, differentiation, and development. For example, they deacetylate non-histone proteins like the tumor suppressor p53, influencing cell cycle progression and DNA damage responses.

Class II HDACs: Shuttling Between Cellular Compartments

The Class II HDACs are a functionally diverse group, divided into two subclasses based on their structure: Class IIa includes HDAC4, HDAC5, HDAC7, and HDAC9, while Class IIb is composed of HDAC6 and HDAC10. Their expression is often more restricted to specific tissues compared to the ubiquitous Class I enzymes. The most prominent characteristic of Class IIa HDACs is their ability to shuttle between the nucleus and the cytoplasm.

This movement is tightly regulated by signaling events within the cell, such as phosphorylation. This nucleocytoplasmic shuttling allows Class II HDACs to act on a broader range of targets beyond histones, including proteins in the cytoplasm. Their regulation by external signals and tissue-specific expression patterns link them to specialized roles like muscle development, neuronal survival, and immune responses. The dynamic localization of these enzymes provides an additional layer of regulatory control over gene expression and cellular behavior.

Class III HDACs: The NAD+-Dependent Sirtuins

Class III HDACs, more commonly known as the sirtuins, are distinguished by their unique catalytic mechanism. As defined by their classification, sirtuins depend on nicotinamide adenine dinucleotide (NAD+), a molecule central to cellular metabolism, to fuel their deacetylase activity. This links their function directly to the metabolic state of the cell.

The sirtuin family (SIRT1–SIRT7) exhibits diversity in its subcellular localization, being found in the nucleus, cytoplasm, and mitochondria. This distribution allows them to regulate a wide array of biological processes. Sirtuins are involved in managing metabolic pathways, orchestrating responses to cellular stress, maintaining genome stability, and influencing aging. By deacetylating non-histone targets, sirtuins connect epigenetic regulation with the cell’s core metabolic and stress-response networks.

Class IV HDACs: The Unique Case of HDAC11

Class IV contains only a single member, HDAC11, making it the smallest and most recently identified class. It was placed in its own distinct category because its sequence and structure contain features of both Class I and Class II HDACs, yet it is phylogenetically separate. The expression of HDAC11 is restricted to specific tissues, primarily the brain, heart, kidney, and muscle, suggesting it performs specialized functions in these organs.

Research has uncovered its roles within the immune system. For instance, HDAC11 is involved in regulating the expression of interleukin 10, a signaling molecule in immune responses, and also plays a part in the development of T cells. Although it is the least characterized of the HDACs, ongoing research shows that in addition to its deacetylase activity, it can remove other types of chemical modifications from proteins, expanding its functional repertoire.