Lysine AcetylationEdit

Lysine acetylation is a reversible chemical modification that attaches an acetyl group to the epsilon amino group of lysine residues on proteins. Once thought to be a narrowly histone-centric mark, it is now understood to be a widespread regulatory mechanism that affects a diverse set of cellular proteins—from chromatin components to metabolic enzymes and signaling factors. The enzymes that add (writers) and remove (erasers) acetyl groups, together with reader proteins that interpret acetyl-lysine marks, create a regulatory network that links metabolism, gene regulation, and cellular signaling in both health and disease. post-translational modification histone acetylation.

Across biology, the acetylation landscape is dynamically governed by cellular metabolism. Acetyl-CoA, a central metabolite produced in mitochondria and cytosol, serves as the donor of acetyl groups, tying a cell’s energy and nutrient status to protein function. This metabolic–epigenetic crosstalk is central to how cells respond to nutrients, stress, and developmental cues. While histone acetylation is the best known example, non-histone lysine acetylation affects transcription factors, metabolic enzymes, cytoskeletal components, and more, broadening the physiological scope of this modification. acetyl-CoA chromatin enzyme regulation.

Biochemical basis and enzymology

Lysine acetylation proceeds through the concerted action of writers, erasers, and readers. The chemistry involves transfer of an acetyl group from acetyl-CoA to the lysine side chain, which neutralizes a portion of the positive charge and can alter protein–protein interactions, stability, localization, or catalytic activity. This chemistry is exploited by specific enzyme families.

Writers: lysine acetyltransferases (KATs)

Lysine acetyltransferases are diverse, with several major families in eukaryotes. Notable examples include:

p300/CBP family, collectively contributing widely to histone and non-histone acetylation. p300 CREBBP
GCN5 and PCAF, which acetylate histones and other substrates. GCN5 PCAF
TIP60 and MOF, among others, with roles in chromatin remodeling and DNA damage response. TIP60 KAT8

These enzymes use acetyl-CoA as the acetyl donor and can target a broad set of lysines across proteins. Their activity integrates signaling pathways, transcriptional programs, and metabolic state. Readers of acetyl-lysine marks include bromodomain-containing proteins that recognize the modification and help recruit transcriptional or chromatin-remodeling complexes. bromodomain BRD4

Erasers: histone deacetylases (HDACs) and sirtuins

Removal of acetyl groups is carried out by histone deacetylases and sirtuins. HDACs are grouped into several classes with distinct substrate specificities and cellular localizations, while sirtuins (Sir2-related enzymes) require NAD+ and link acetylation dynamics to cellular energy status. Examples include:

Classical HDACs (class I–II) that act on a variety of histone and non-histone substrates. HDAC1 HDAC2 HDAC3 HDAC4 HDAC7
Sirtuins (class III HDACs) such as SIRT1–SIRT7, which have unique regulatory roles in metabolism, stress responses, and aging. SIRT1 SIRT2 SIRT3

Readers and the regulatory network

Proteins with acetyl-lysine reader domains (notably bromodomains) interpret acetyl marks and help translate the chemical signal into functional outcomes, such as transcriptional activation, chromatin remodeling, or alterations in protein interactions. bromodomain BRD2 BRD3

Roles in chromatin, transcription, and non-histone regulation

In chromatin, histone acetylation weakens interactions between histone tails and DNA, yielding a more open chromatin state that facilitates transcription factor binding and transcriptional initiation. This histone code component works alongside other histone modifications in regulating access to genetic information. Histone acetylation is also involved in DNA damage responses and chromatin remodeling, underscoring its role in genome maintenance. histone acetylation chromatin DNA damage response

Beyond histones, acetylation modulates a wide range of non-histone proteins, including transcription factors like p53 and NF-κB, metabolic enzymes such as acetyl-CoA synthetases and glycolytic enzymes, and cytoskeletal components. This broad substrate scope means acetylation can impact cell cycle control, metabolism, signaling networks, and stress responses. Examples include p53 acetylation affecting its transcriptional activity and stability, and acetylation of metabolic enzymes altering their catalytic properties. p53 NF-κB ACSS2 metabolic regulation

The acetylation state of a protein is influenced by cellular energy status and nutrient availability, as well as by the activity of writers and erasers. This creates a dynamic regulatory axis where metabolism informs gene expression and enzyme function, and vice versa. acetyl-CoA enzyme regulation

Metabolism, signaling, and disease relevance

Because acetylation uses a key metabolic substrate, it serves as a nexus between metabolism and regulation of gene expression and protein function. Fluctuations in acetyl-CoA availability can propagate changes in acetylation patterns, with downstream effects on transcriptional programs, metabolic flux, and stress responses. This makes lysine acetylation a focal point for understanding metabolic diseases, cancer, and neurodegenerative disorders, and it has driven interest in targeting acetylation pathways therapeutically. Drug classes that influence this system, such as histone deacetylase inhibitors, have reached clinical use in oncology and are active areas of research in other diseases. acetyl-CoA HDAC inhibitor cancer neurodegenerative disease

Techniques and data resources

The acetylation landscape is mapped through proteomics, biochemistry, and targeted assays. Mass spectrometry-based proteomics identifies acetylation sites across the proteome, while antibodies against acetyl-lysine provide site-specific or global readouts. Bioinformatic approaches integrate acetylation data with other post-translational modifications to model regulatory networks. Researchers also study the functional consequences of acetylation by mutating lysine residues or modulating writer/eraser activities. mass spectrometry antibody proteomics

Clinical and translational landscape

Pharmacological manipulation of acetylation has yielded clinically useful agents, most notably histone deacetylase (HDAC) inhibitors used in cancer therapy. These drugs can alter gene expression programs and affect tumor cell growth, but they often have broad effects and side effects that require careful patient selection and biomarker guidance. BRD (bromodomain) inhibitors, which target readers of acetyl-lysine marks, are also under development to modulate transcriptional programs in cancer and other diseases. The translational story emphasizes both the therapeutic promise and the need for rigorous evaluation of efficacy, safety, and specificity. HDAC inhibitor bromodomain cancer

Debates and controversies

As with many areas of epigenetics, lysine acetylation sits at the center of debates about causation, interpretation, and clinical translation. Key points of contention include:

Causality vs correlation: Observed changes in acetylation accompanying a disease state do not automatically prove that acetylation drives disease; disentangling cause from consequence requires precise perturbations and causal experiments. Critics emphasize the need for rigorous, mechanistic demonstrations beyond correlative data. causality translational research
Functional specificity: Given the broad range of substrates for KATs and HDACs, there is ongoing debate about how specific acetylation events are shaped by particular writers, erasers, and reader complexes, and how much functional redundancy exists. KAT HDAC
Therapeutic targeting: While HDAC inhibitors and bromodomain inhibitors show promise, their broad activity can lead to off-target effects and toxicity. The challenge is to identify patient populations, biomarkers, and combination strategies that maximize benefit while minimizing harm. HDAC inhibitor bromodomain inhibitor
Epigenetics and social discourse: Some critics argue that sensational interpretations of epigenetic data can be used to make deterministic claims about behavior or social outcomes. Proponents stress that robust epigenetic mechanisms do not erase plasticity and that environmental and lifestyle factors continue to shape biology. From a practical standpoint, policy should rest on strong evidence and avoid overreach. Critics of inflated narratives contend that scientific complexity and uncertainty should not be replaced by deterministic or identity-based explanations. Proponents maintain that cautious, well-supported findings can inform public health and medicine without surrendering nuance. epigenetics public policy