Histone Acetylation

1. What Is Histone Acetylation？

Histone acetylation refers to the process of adding an acetyl group to the lysine residues on the N-terminal tail of histone proteins ^[1]. Negative charges of added acetyl groups neutralize lysines' positive charges, which results in a weakened histone-DNA interaction, leading to a more relaxed chromatin structure that facilitates the access of transcription factors to genomic sequences, thus increasing gene expression.

Histone acetylation has been detected on various histone proteins. Specifically, H3 displays acetylation on residues K4, K9, K14, K18, K23, K27, K36, and K56, while H4 showcases acetylation on K5, K8, K12, K16, K20, and K91. Additionally, H2A and H2B also undergo lysine acetylation, with H2A being modified at K5 and K9, and H2B experiencing acetylation at K5, K12, K15, K16, K20, and K120.

2. Enzymes or Proteins Involved in Histone Acetylation

Histone acetylation is a dynamic and reversible process synergistically regulated by histone acetylation modulators (HAMs) including writers (histone acetyltransferases), readers, and erasers (histone deacetylases) that add, recognize, and remove the acetyl group, respectively. This dynamic interplay between HATs and HDACs regulates the balance of histone acetylation, ensuring precise control of gene expression patterns.

2.1 Histone Acetyltransferases (HATs)

HATs, also called "writers", are responsible for transferring an acetyl group (-COCH3) from acetyl CoA to the ε-amino group of target lysine residues of H3 or H4 [2]. HATS also acetylate various non-histone substrates, thus they are generally categorized as lysine acetyltransferases (KATs).

HATs are classified into two major categories based on their cellular localization: type A HATs, which are located in the nucleus and acetylate nucleosomal histones and other chromatin-associated proteins, and type B HATs, which are situated in the cytoplasm and specifically acetylate free newly synthesized histones, having no direct impact on transcription.

The Table information is cited from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881052/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311713/

2.2 Histone Deacetylases (HDACs)

HDACs, also known as "erasers", are enzymes that remove acetyl groups from acetylated histones. Histone deacetylation reduces DNA accessibility by exposing the positive charge of the lysine residues, which enables interactions between DNA and the histone tail, leading to chromatin compaction and a more condensed chromatin structure, effectively repressing gene expression.

HDACs are vital for various physiological processes, including development and cellular homeostasis, while also contributing to pathological conditions such as neurodegenerative disorders, genetic diseases, and cancer.

In humans, there are four classes of HDAC enzymes based on their sequence homology to yeast ^[4]. Class I HDACs include HDAC1-3 and HDAC8. Class II HDACs consist of HDAC4-7, HDAC9, and HDAC10 ^[5-7]. The Class III HDACs, also known as sirtuins, include SIRT1-7 ^[8,9], which require the NAD+ cofactor for activity. The Class IV HDAC only has an enzyme HDAC11 ^[10]. Class I, II, and IV HDACs are Zn2+-dependent amidohydrolases.

The Table information is cited from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970420/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444376/

HDACs are expressed in various tumors and function differently. Hypoacetylation is a prevalent characteristic observed in numerous cancers. Class I and II HDACs are generally considered oncoproteins that interact with substrates and co-repressors to regulate gene expression, promoting tumorigenesis and cancer development. However, SIRTs (Class III HDACs) can function as both oncoproteins and tumor suppressors, depending on the context.

2.3 Readers

Histone acetylation readers specifically recognize acetylated lysines and recruit transcription factors and other regulatory proteins to bind to the DNA, initiating transcription, thus activating gene expression ^[17,18]. They are usually bromodomain (BRD)-containing proteins or themselves acetyllysine-binding proteins, such as the BRDs and extra-terminal domain (BET) family, and are responsible for interpreting the acetylation signal into specific changes in gene expression and chromatin remodeling.

BRDs stand out as the sole protein group capable of recognizing and binding acetylated histone lysine residues. They are extensively distributed throughout various tissues and categorized into eight families based on sequence or structural similarity, each displaying diverse activities such as histone modification and chromatin remodeling.

The Table information is cited from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686570/

3. Mechanism of Histone Acetylation

HATs acetylate histone lysine residues, which decreases the electrostatic interactions between histones and DNA, leading to a relaxed chromatin structure. Consequently, DNA becomes exposed, facilitating the recruitment of transcriptional activators (TA) to genomic sequences and activating gene expression.

Conversely, HDACs can interact with transcriptional repressor (TR) complexes to remove these acetyl modifications. This enhances the electrostatic interactions between DNA and histones, leading to compact chromatin that represses transcription. Maintaining a balance between histone acetylation and deacetylation is crucial for proper gene expression.

Figure 1. Histone acethylation and deacetylation mechanism

The picture is cited from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820808/

4. Function of Histone Acetylation

A large amount of research data demonstrated that histone acetylationis widespread in cells and is involved in various cellular activities, including regulation of nucleosome assembly, folding and deconvolution of chromatin, gene transcription, DNA damage repair, cell cycle, and apoptosis ^[19].

5. Crosstalk with Other Modifications

There exists intricate crosstalk between histone acetylation and other histone modifications, such as methylation, phosphorylation, and ubiquitination. They cooperate or antagonize each other, influencing chromatin structure and gene expression patterns.

In the budding yeast Saccharomyces cerevisiae, Snf1 kinase-mediated H3S10ph promotes the acetylation of H3K14 by the Gcn5 acetyltransferase, amplifying the interaction between histone H3 and the 14-3-3 proteins Bmh1 and Bmh2 during gene activation ^[20]. In mammalian cells, H3K18ac and H3K23ac facilitate CARM1 methyltransferase-mediated H3R17 methylation, leading to activation of estrogen-responsive genes ^[21].

Histone modification crosstalk can also play a role in removing specific modifications. For instance, in budding yeast, the Set2 methyltransferase, which associates with RNA polymerase II, methylates H3K36, directing nucleosomes for deacetylation of both H3 and H4 by the Rpd3S deacetylase complex following RNA polymerase passage ^[22].

Wojcik, F. et al. demonstrated that acetylation of H2A on multiple sites, including K5, K9, K13, and K15 inhibits the ubiquitylation of H2BK120 ^[23].

6. Development and Disease

Histone acetylation is involved in numerous biological processes, including development, differentiation, and response to environmental cues. Dysregulation of histone acetylation has been associated with various diseases, such as cancer, neurological disorders, and metabolic disorders, highlighting its significance in disease pathogenesis.

Aberrant histone acetylation patterns have been observed in cancer cells, contributing to uncontrolled cell growth and tumorigenesis. HDAC inhibitors, which restore proper acetylation patterns, have shown promise as potential therapies for certain cancers, offering a novel approach to target cancer cells while sparing normal cells.

In neurodegenerative diseases, such as Alzheimer's and Parkinson's, disturbances in histone acetylation have been linked to changes in gene expression patterns associated with neuronal survival and function. Dysregulated histone acetylation may contribute to neurodegeneration and disease progression.

Moreover, histone acetylation is also associated with metabolic disorders, where it can impact the expression of genes involved in glucose metabolism and lipid homeostasis. Epigenetic changes in response to diet and environmental factors may contribute to metabolic dysregulation and obesity-related diseases.

Together, HATs, HDACs, and BRDs form a complex regulatory network that controls the acetylation status of histones and, consequently, the accessibility of genes for transcription. This epigenetic machinery plays a critical role in various biological processes, including development, differentiation, and response to environmental cues. Dysregulation of these enzymes can lead to aberrant gene expression patterns and is associated with several diseases, making them promising targets for therapeutic interventions and drug development.