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Science Advances Jan 2022Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with...
Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown. Here, we report the systematic evaluation of zinc- and nicotinamide adenine dinucleotide–dependent histone deacetylases (HDACs) for their ability to cleave ε--L-lactyllysine marks. Our screens identified HDAC1–3 and SIRT1–3 as delactylases in vitro. HDAC1–3 show robust activity toward not only K(L-la) but also K(D-la) and diverse short-chain acyl modifications. We further confirmed the de-L-lactylase activity of HDACs 1 and 3 in cells. Together, these data suggest that histone lactylation is installed and removed by regulatory enzymes as opposed to spontaneous chemical reactivity. Our results therefore represent an important step toward full characterization of this pathway’s regulatory elements.
Topics: Acetylation; Histone Deacetylases; Histones; Lysine
PubMed: 35044827
DOI: 10.1126/sciadv.abi6696 -
Cellular and Molecular Life Sciences :... May 2021Crop productivity is directly dependent on the growth and development of plants and their adaptation during different environmental stresses. Histone acetylation is an... (Review)
Review
Crop productivity is directly dependent on the growth and development of plants and their adaptation during different environmental stresses. Histone acetylation is an epigenetic modification that regulates numerous genes essential for various biological processes, including development and stress responses. Here, we have mainly discussed the impact of histone acetylation dynamics on vegetative growth, flower development, fruit ripening, biotic and abiotic stress responses. Besides, we have also emphasized the information gaps which are obligatory to be examined for understanding the complete role of histone acetylation dynamics in plants. A comprehensive knowledge about the histone acetylation dynamics will ultimately help to improve stress resistance and reduce yield losses in different crops due to climate changes.
Topics: Acetylation; Histones; Humans; Plant Development; Plants; Stress, Physiological
PubMed: 33638653
DOI: 10.1007/s00018-021-03794-x -
Molecular Aspects of Medicine Aug 2022Post-translational modifications (PTMs) have been proposed as a link between the oxidative stress-inflammation-ageing trinity, thereby affecting several hallmarks of... (Review)
Review
Post-translational modifications (PTMs) have been proposed as a link between the oxidative stress-inflammation-ageing trinity, thereby affecting several hallmarks of ageing. Phosphorylation, acetylation, and ubiquitination cover >90% of all the reported PTMs. Several of the main PTMs are involved in normal "healthy" ageing and in different age-related diseases, for instance neurodegenerative, metabolic, cardiovascular, and bone diseases, as well as cancer and chronic kidney disease. Ultimately, data from human rare progeroid syndromes, but also from long-living animal species, imply that PTMs are critical regulators of the ageing process. Mechanistically, PTMs target epigenetic and non-epigenetic pathways during ageing. In particular, epigenetic histone modification has critical implications for the ageing process and can modulate lifespan. Therefore, PTM-based therapeutics appear to be attractive pharmaceutical candidates to reduce the burden of ageing-related diseases. Several phosphorylation and acetylation inhibitors have already been FDA-approved for the treatment of other diseases and offer a unique potential to investigate both beneficial effects and possible side-effects. As an example, the most well-studied senolytic compounds dasatinib and quercetin, which have already been tested in Phase 1 pilot studies, also act as kinase inhibitors, targeting cellular senescence and increasing lifespan. Future studies need to carefully determine the best PTM-based candidates for the treatment of the "diseasome of ageing".
Topics: Acetylation; Aging; Animals; Histones; Humans; Oxidative Stress; Phosphorylation; Protein Processing, Post-Translational
PubMed: 35689974
DOI: 10.1016/j.mam.2022.101099 -
Nature Communications Dec 2022Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle...
Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition.
Topics: Acetylation; Histones; Epigenesis, Genetic; Cell Nucleus; Mitochondria
PubMed: 36460681
DOI: 10.1038/s41467-022-35199-0 -
Molecular Neurodegeneration Jul 2023Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer's disease...
BACKGROUND
Nuclear acetyl-CoA pools govern histone acetylation that controls synaptic plasticity and contributes to cognitive deterioration in patients with Alzheimer's disease (AD). Nuclear acetyl-CoA pools are generated partially from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). However, the underlying mechanism of histone acetylation dysregulation in AD remains poorly understood.
METHODS
We detected ACSS2 expression and histone acetylation levels in the brains of AD patients and 5 × FAD mice. When we altered ACSS2 expression by injecting adeno-associated virus into the dorsal hippocampus of 5 × FAD mice and replenished ACSS2 substrate (acetate), we observed changes in cognitive function by Morris water maze. We next performed RNA-seq, ChIP-qPCR, and electrophysiology to study molecular mechanism underlying ACSS2-mediated spatial learning and memory in 5 × FAD mice.
RESULTS
We reported that ACSS2 expression and histone acetylation (H3K9, H4K12) were reduced in the hippocampus and prefrontal cortex of 5 × FAD mice. Reduced ACSS2 levels were also observed in the temporal cortex of AD patients. 5 × FAD mice exhibited a low enrichment of acetylated histones on the promoters of NMDARs and AMPARs, together with impaired basal and activity-dependent synaptic plasticity, all of which were rescued by ACSS2 upregulation. Moreover, acetate replenishment enhanced ac-H3K9 and ac-H4K12 in 5 × FAD mice, leading to an increase of NMDARs and AMPARs and a restoration of synaptic plasticity and cognitive function in an ACSS2-dependent manner.
CONCLUSION
ACSS2 is a key molecular switch of cognitive impairment and that targeting ACSS2 or acetate administration may serve as a novel therapeutic strategy for the treatment of intermediate or advanced AD. Nuclear acetyl-CoA pools are generated partly from local acetate that is metabolized by acetyl-CoA synthetase 2 (ACSS2). Model depicts that ACSS2 expression is downregulated in the brains of 5×FAD model mice and AD patients. Of note, ACSS2 downregulation mediates a reduction in ionotropic glutamate receptor expression through histone acetylation, which exacerbates synaptic plasticity impairment in AD. These deficits can be rescued by ACSS2 upregulation or acetate supplementation (GTA, an FDA-approved food additive), which may serve as a promising therapeutic strategy for AD treatment.
Topics: Animals; Mice; Acetyl Coenzyme A; Acetylation; Alzheimer Disease; Cognition; Disease Models, Animal; Histones; Acetate-CoA Ligase
PubMed: 37438762
DOI: 10.1186/s13024-023-00625-4 -
Cell Stem Cell Apr 2021Histone crotonylation is a non-acetyl histone lysine modification that is as widespread as acetylation. However, physiological functions associated with histone...
Histone crotonylation is a non-acetyl histone lysine modification that is as widespread as acetylation. However, physiological functions associated with histone crotonylation remain almost completely unknown. Here we report that histone crotonylation is crucial for endoderm differentiation. We demonstrate that key crotonyl-coenzyme A (CoA)-producing enzymes are specifically induced in endodermal cells during differentiation of human embryonic stem cells (hESCs) in vitro and in mouse embryos, where they function to increase histone crotonylation and enhance endodermal gene expression. Chemical enhancement of histone crotonylation promotes endoderm differentiation of hESCs, whereas deletion of crotonyl-CoA-producing enzymes reduces histone crotonylation and impairs meso/endoderm differentiation in vitro and in vivo. Our study uncovers a histone crotonylation-mediated mechanism that promotes endodermal commitment of pluripotent stem cells, which may have important implications for therapeutic strategies against a number of human diseases.
Topics: Acetylation; Animals; Cell Differentiation; Histones; Human Embryonic Stem Cells; Lysine; Mice; Protein Processing, Post-Translational
PubMed: 33450185
DOI: 10.1016/j.stem.2020.12.009 -
Journal of the American Chemical Society Mar 2023The reversible acetylation of histone lysine residues is controlled by the action of acetyltransferases and deacetylases (HDACs), which regulate chromatin structure and...
The reversible acetylation of histone lysine residues is controlled by the action of acetyltransferases and deacetylases (HDACs), which regulate chromatin structure and gene expression. The sirtuins are a family of NAD-dependent HDAC enzymes, and one member, sirtuin 6 (Sirt6), influences DNA repair, transcription, and aging. Here, we demonstrate that Sirt6 is efficient at deacetylating several histone H3 acetylation sites, including its canonical site Lys9, in the context of nucleosomes but not free acetylated histone H3 protein substrates. By installing a chemical warhead at the Lys9 position of histone H3, we trap a catalytically poised Sirt6 in complex with a nucleosome and employ this in cryo-EM structural analysis. The structure of Sirt6 bound to a nucleosome reveals extensive interactions between distinct segments of Sirt6 and the H2A/H2B acidic patch and nucleosomal DNA, which accounts for the rapid deacetylation of nucleosomal H3 sites and the disfavoring of histone H2B acetylation sites. These findings provide a new framework for understanding how HDACs target and regulate chromatin.
Topics: Nucleosomes; Histones; Chromatin; Sirtuins; Acetylation; Glycosyltransferases; Catalysis
PubMed: 36930461
DOI: 10.1021/jacs.2c13512 -
Cell Mar 2012Bromodomains (BRDs) are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks....
Bromodomains (BRDs) are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations of marks rather than singly acetylated sequences. We further uncovered a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4. These data provide a foundation for structure-based drug design of specific inhibitors for this emerging target family.
Topics: Acetylation; Amino Acid Sequence; Animals; Crystallography, X-Ray; Genome, Human; Histones; Humans; Lysine; Models, Molecular; Molecular Sequence Data; Phylogeny; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Protein Structure, Tertiary; Proteome
PubMed: 22464331
DOI: 10.1016/j.cell.2012.02.013 -
Current Biology : CB Apr 2023Q&A with Asifa Akhtar who studies histone acetylation and genome regulation.
Q&A with Asifa Akhtar who studies histone acetylation and genome regulation.
Topics: Histones; Genome; Acetylation
PubMed: 37098326
DOI: 10.1016/j.cub.2023.03.040 -
British Journal of Pharmacology Jan 2021Epigenetic mechanisms, including DNA methylation and histone post-translational modifications (PTMs), have been known to regulate chromatin structure and... (Review)
Review
Epigenetic mechanisms, including DNA methylation and histone post-translational modifications (PTMs), have been known to regulate chromatin structure and lineage-specific gene expression during cardiovascular development and disease. However, alterations in the landscape of histone PTMs and their contribution to the pathogenesis of incurable cardiovascular diseases such as pulmonary hypertension (PH) and associated right heart failure (RHF) remain largely unexplored. This review focusses on the studies in PH and RHF that investigated the gene families that write (histone acetyltransferases), read (bromodomain-containing proteins) or erase (histone deacetylases [HDACs] and sirtuins [SIRT]) acetyl moieties from the ε-amino group of lysine residues of histones and non-histone proteins. Analysis of cells and tissues isolated from the in vivo preclinical models of PH and human pulmonary arterial hypertension not only confirmed significant alterations in the expression levels of multiple HDACs, SIRT1, SIRT3 and BRD4 proteins but also demonstrated their strong association to proliferative, inflammatory and fibrotic phenotypes linked to the pathological vascular remodelling process. Due to the reversible nature of post-translational protein acetylation, the therapeutic efficacy of numerous small-molecule inhibitors (vorinostat, valproic acid, sodium butyrate, mocetinostat, entinostat, tubastatin A, apabetalone, JQ1 and resveratrol) have been evaluated in different preclinical models of cardiovascular disease, which revealed the promising therapeutic benefits of targeting histone acetylation pathways in the attenuation of cardiac hypertrophy, fibrosis, left heart dysfunction, PH and RHF. This review also emphasizes the need for deeper molecular insights into the contribution of epigenetic changes to PH pathogenesis and therapeutic evaluation of isoform-specific modulation in ex vivo and in vivo models of PH and RHF. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.
Topics: Acetylation; Cell Cycle Proteins; Histones; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Nuclear Proteins; Protein Processing, Post-Translational; Transcription Factors
PubMed: 31749139
DOI: 10.1111/bph.14932