Protein lysine acetylation is a critical post-translational modification involved in a wide range of biological processes. To date, about 20,000 acetylation sites of Homo sapiens were identified ...through mass spectrometry–based proteomic technology, but more than 95% of them have unclear functional annotations because of the lack of existing prioritization strategy to assess the functional importance of the acetylation sites on large scale. Hence, we established a lysine acetylation functional evaluating model (LAFEM) by considering eight critical features surrounding lysine acetylation site to high-throughput estimate the functional importance of given acetylation sites. This was achieved by selecting one of the random forest models with the best performance in 10-fold cross-validation on undersampled training dataset. The global analysis demonstrated that the molecular environment of acetylation sites with high acetylation functional scores (AFSs) mainly had the features of larger solvent-accessible surface area, stronger hydrogen bonding–donating abilities, near motif and domain, higher homology, and disordered degree. Importantly, LAFEM performed well in validation dataset and acetylome, showing good accuracy to screen out fitness directly relevant acetylation sites and assisting to explain the core reason for the difference between biological models from the perspective of acetylome. We further used cellular experiments to confirm that, in nuclear casein kinase and cyclin-dependent kinase substrate 1, acetyl-K35 with higher AFS was more important than acetyl-K9 with lower AFS in the proliferation of A549 cells. LAFEM provides a prioritization strategy to large scale discover the fitness directly relevant acetylation sites, which constitutes an unprecedented resource for better understanding of functional acetylome.
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•LAFEM is the first prioritization strategy to evaluate functional acetylome.•LAFEM enriches functional annotations of 15,410 acetylation sites.•Eight molecular features in LAFEM are related to the function of acetylation site.•Assessment of acetylation sites by LAFEM provide support for quantitative acetylomics.
Not all acetylation sites contribute equally to fitness, which disturbs us to find out the core reason between different biological models. In fact, it is insufficient to evaluate functional acetylation sites only relying on quantification acetylome. Therefore, we developed LAFEM to comprehensively consider the molecular environment of individual acetylation sites. The LAFEM score of acetylation site is beneficial to the following experimental validation and the discover of core biological regularity.
Loss of cellular homeostasis during aging results in altered tissue functions and leads to a general decline in fitness and, ultimately, death. As animals age, the control of gene expression, which ...is orchestrated by multiple epigenetic factors, degenerates. In parallel, metabolic activity and mitochondrial protein acetylation levels also change. These two hallmarks of aging are effectively linked through the accumulating evidence that histone acetylation patterns are susceptible to alterations in key metabolites such as acetyl-CoA and NAD+, allowing chromatin to function as a sensor of cellular metabolism. In this review we discuss experimental data supporting these connections and provide a context for the possible medical and physiological relevance.
Aging animals show global, often nonspecific changes in gene expression.
Epigenetic marks such as the acetylation of histones change substantially when animals age. These changes can already be observed when animals reach midlife.
Changes in key metabolites during early aging result in changes in post-translational modifications of metabolic enzymes. This potentially leads to a transient increase in metabolic activity when animals reach midlife.
Age-dependent changes of histone acetylation are coupled to altered metabolic activity in aging animals, which could potentially influence global gene expression.
Mutations in genes that link metabolism and chromatin, such as lysine acetyl transferases (KATs), lysine deacetylases (KDACs) (sirtuins), and ATP citrate lyase (ACLY/ATPCL), have been shown to influence lifespan and the development of age-associated diseases.
The association of histone modification changes with autism spectrum disorder (ASD) has not been systematically examined. We conducted a histone acetylome-wide association study (HAWAS) by performing ...H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) on 257 postmortem samples from ASD and matched control brains. Despite etiological heterogeneity, ≥68% of syndromic and idiopathic ASD cases shared a common acetylome signature at >5,000 cis-regulatory elements in prefrontal and temporal cortex. Similarly, multiple genes associated with rare genetic mutations in ASD showed common “epimutations.” Acetylome aberrations in ASD were not attributable to genetic differentiation at cis-SNPs and highlighted genes involved in synaptic transmission, ion transport, epilepsy, behavioral abnormality, chemokinesis, histone deacetylation, and immunity. By correlating histone acetylation with genotype, we discovered >2,000 histone acetylation quantitative trait loci (haQTLs) in human brain regions, including four candidate causal variants for psychiatric diseases. Due to the relative stability of histone modifications postmortem, we anticipate that the HAWAS approach will be applicable to multiple diseases.
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•Histone acetylation population study of ASD and control brain samples•Discovery of ASD-specific epigenetic signature•Similar epigenomic aberrations in syndromic and idiopathic ASD•Thousands of QTLs are discovered
As part of the IHEC consortium, this study characterized histone acetylation patterns in brain samples from patients with autism spectrum disorder (ASD), uncovering a distinct epigenetic signature in ASD and providing a rich resource for future molecular analyses of ASD patients. Explore the Cell Press IHEC web portal at http://www.cell.com/consortium/IHEC.
The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators. Here, we combined quantitative proteomics with CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, ...and gene knockout to reveal a comprehensive map of regulated acetylation sites and their dynamic turnover rates. CBP/p300 acetylates thousands of sites, including signature histone sites and a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Time-resolved acetylome analyses identified a subset of CBP/p300-regulated sites with very rapid (<30 min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions and for understanding the impact of small-molecule inhibitors targeting its catalytic and bromodomain activities.
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•Quantitative acetylomics reveals thousands of in vivo substrates of CBP/p300•CBP/p300-regulated sites display rapid deacetylation kinetics•Histone H2B is prominently acetylated by CBP/p300 at multiple sites•Rapid turnover of CBP/p300-catalyzed acetylation controls gene transcription
A comprehensive look at CBP/p300 acetylation reveals dynamic changes that shape the regulation of protein function and gene expression.
Issue Information
The FEBS journal,
01/2024, Letnik:
291, Številka:
2
Journal Article
Recenzirano
Cover IllustrationOverview of nuclear receptors regulated by acetylation. Image provided by Richard G. Pestell and colleagues, authors of the State‐of‐the‐Art Review included in this issue, pages ...217–236.
Protein Acetylation in Bacteria VanDrisse, Chelsey M; Escalante-Semerena, Jorge C
Annual review of microbiology,
09/2019, Letnik:
73
Journal Article
Recenzirano
Odprti dostop
Acetylation is a posttranslational modification conserved in all domains of life that is carried out by
-acetyltransferases. While acetylation can occur on
-amino groups, this review will focus on
...-acetylation of lysyl residues and how the posttranslational modification changes the cellular physiology of bacteria. Up until the late 1990s, acetylation was studied in eukaryotes in the context of chromatin maintenance and gene expression. At present, bacterial protein acetylation plays a prominent role in central and secondary metabolism, virulence, transcription, and translation. Given the diversity of niches in the microbial world, it is not surprising that the targets of bacterial protein acetyltransferases are very diverse, making their biochemical characterization challenging. The paradigm for acetylation in bacteria involves the acetylation of acetyl-CoA synthetase, whose activity must be tightly regulated to maintain energy charge homeostasis. While this paradigm has provided much mechanistic detail for acetylation and deacetylation, in this review we discuss advances in the field that are changing our understanding of the physiological role of protein acetylation in bacteria.
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