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Proceedings of the National Academy of... Apr 2023Epigenetic modifications of chromatin play a critical role in regulating the fidelity of the genetic code and in controlling the translation of genetic information into...
Epigenetic modifications of chromatin play a critical role in regulating the fidelity of the genetic code and in controlling the translation of genetic information into the protein components of the cell. One key posttranslational modification is acetylation of histone lysine residues. Molecular dynamics simulations, and to a smaller extent experiment, have established that lysine acetylation increases the dynamics of histone tails. However, a systematic, atomic resolution experimental investigation of how this epigenetic mark, focusing on one histone at a time, influences the structural dynamics of the nucleosome beyond the tails, and how this translates into accessibility of protein factors such as ligases and nucleases, has yet to be performed. Herein, using NMR spectroscopy of nucleosome core particles (NCPs), we evaluate the effects of acetylation of each histone on tail and core dynamics. We show that for histones H2B, H3, and H4, the histone core particle dynamics are little changed, even though the tails have increased amplitude motions. In contrast, significant increases to H2A dynamics are observed upon acetylation of this histone, with the docking domain and L1 loop particularly affected, correlating with increased susceptibility of NCPs to nuclease digestion and more robust ligation of nicked DNA. Dynamic light scattering experiments establish that acetylation decreases inter-NCP interactions in a histone-dependent manner and facilitates the development of a thermodynamic model for NCP stacking. Our data show that different acetylation patterns result in nuanced changes to NCP dynamics, modulating interactions with other protein factors, and ultimately controlling biological output.
Topics: Histones; Nucleosomes; Acetylation; Lysine; Protein Processing, Post-Translational
PubMed: 37011222
DOI: 10.1073/pnas.2301063120 -
The Journal of Biological Chemistry Jun 2023The ability of cells to store and rapidly mobilize energy reserves in response to nutrient availability is essential for survival. Breakdown of carbon stores produces...
The ability of cells to store and rapidly mobilize energy reserves in response to nutrient availability is essential for survival. Breakdown of carbon stores produces acetyl-CoA (AcCoA), which fuels essential metabolic pathways and is also the acyl donor for protein lysine acetylation. Histones are abundant and highly acetylated proteins, accounting for 40% to 75% of cellular protein acetylation. Notably, histone acetylation is sensitive to AcCoA availability, and nutrient replete conditions induce a substantial accumulation of acetylation on histones. Deacetylation releases acetate, which can be recycled to AcCoA, suggesting that deacetylation could be mobilized as an AcCoA source to feed downstream metabolic processes under nutrient depletion. While the notion of histones as a metabolic reservoir has been frequently proposed, experimental evidence has been lacking. Therefore, to test this concept directly, we used acetate-dependent, ATP citrate lyase-deficient mouse embryonic fibroblasts (Acly MEFs), and designed a pulse-chase experimental system to trace deacetylation-derived acetate and its incorporation into AcCoA. We found that dynamic protein deacetylation in Acly MEFs contributed carbons to AcCoA and proximal downstream metabolites. However, deacetylation had no significant effect on acyl-CoA pool sizes, and even at maximal acetylation, deacetylation transiently supplied less than 10% of cellular AcCoA. Together, our data reveal that although histone acetylation is dynamic and nutrient-sensitive, its potential for maintaining cellular AcCoA-dependent metabolic pathways is limited compared to cellular demand.
Topics: Animals; Mice; Acetates; Acetyl Coenzyme A; Acetylation; Carbon; Fibroblasts; Histones; Cells, Cultured
PubMed: 37142219
DOI: 10.1016/j.jbc.2023.104772 -
ELife May 2023In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact...
In nucleosomes, histone N-terminal tails exist in dynamic equilibrium between free/accessible and collapsed/DNA-bound states. The latter state is expected to impact histone N-termini availability to the epigenetic machinery. Notably, H3 tail acetylation (e.g. K9ac, K14ac, K18ac) is linked to increased H3K4me3 engagement by the BPTF PHD finger, but it is unknown if this mechanism has a broader extension. Here, we show that H3 tail acetylation promotes nucleosomal accessibility to other H3K4 methyl readers, and importantly, extends to H3K4 writers, notably methyltransferase MLL1. This regulation is not observed on peptide substrates yet occurs on the H3 tail, as determined with fully-defined heterotypic nucleosomes. In vivo, H3 tail acetylation is directly and dynamically coupled with H3K4 methylation levels. Together, these observations reveal an acetylation 'chromatin switch' on the H3 tail that modulates read-write accessibility in nucleosomes and resolves the long-standing question of why H3K4me3 levels are coupled with H3 acetylation.
Topics: Chromatin; Histones; Nucleosomes; Methylation; Acetylation
PubMed: 37204295
DOI: 10.7554/eLife.82596 -
Molecular Cell Dec 2022Cell lineage specification is accomplished by a concerted action of chromatin remodeling and tissue-specific transcription factors. However, the mechanisms that induce...
Cell lineage specification is accomplished by a concerted action of chromatin remodeling and tissue-specific transcription factors. However, the mechanisms that induce and maintain appropriate lineage-specific gene expression remain elusive. Here, we used an unbiased proteomics approach to characterize chromatin regulators that mediate the induction of neuronal cell fate. We found that Tip60 acetyltransferase is essential to establish neuronal cell identity partly via acetylation of the histone variant H2A.Z. Despite its tight correlation with gene expression and active chromatin, loss of H2A.Z acetylation had little effect on chromatin accessibility or transcription. Instead, loss of Tip60 and acetyl-H2A.Z interfered with H3K4me3 deposition and activation of a unique subset of silent, lineage-restricted genes characterized by a bivalent chromatin configuration at their promoters. Altogether, our results illuminate the mechanisms underlying bivalent chromatin activation and reveal that H2A.Z acetylation regulates neuronal fate specification by establishing epigenetic competence for bivalent gene activation and cell lineage transition.
Topics: Histones; Acetylation; Transcriptional Activation; Chromatin; Protein Processing, Post-Translational; Nucleosomes
PubMed: 36417913
DOI: 10.1016/j.molcel.2022.11.002 -
Biomedicine & Pharmacotherapy =... Sep 2023Histone lysine crotonylation was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the... (Review)
Review
Histone lysine crotonylation was first identified as a new type of post-translational modification in 2011. In recent years, prominent progress has been made in the study of histone and nonhistone crotonylation in reproduction, development, and disease. Although the regulatory enzyme systems and targets of crotonylation partially overlap with those of acetylation, the peculiar CC bond structure of crotonylation suggests that crotonylation may have specific biological functions. In this review, we summarize the latest research progress regarding crotonylation, especially its regulatory factors and relationship with diseases, which suggest further research directions for crotonylation and provide new ideas for developing disease intervention and treatment regimens.
Topics: Histones; Lysine; Acetylation; Protein Processing, Post-Translational
PubMed: 37392654
DOI: 10.1016/j.biopha.2023.115108 -
Cells Jun 2022Mitochondrial protein acetylation is associated with a host of diseases including cancer, Alzheimer's, and metabolic syndrome. Deciphering the mechanisms regarding how... (Review)
Review
Mitochondrial protein acetylation is associated with a host of diseases including cancer, Alzheimer's, and metabolic syndrome. Deciphering the mechanisms regarding how protein acetylation contributes to disease pathologies remains difficult due to the complex diversity of pathways targeted by lysine acetylation. Specifically, protein acetylation is thought to direct feedback from metabolism, whereby nutritional status influences mitochondrial pathways including beta-oxidation, the citric acid cycle, and the electron transport chain. Acetylation provides a crucial connection between hepatic metabolism and mitochondrial function. Dysregulation of protein acetylation throughout the cell can alter mitochondrial function and is associated with numerous liver diseases, including non-alcoholic and alcoholic fatty liver disease, steatohepatitis, and hepatocellular carcinoma. This review introduces biochemical mechanisms of protein acetylation in the regulation of mitochondrial function and hepatic diseases and offers a viewpoint on the potential for targeted therapies.
Topics: Acetylation; Mitochondria; Mitochondrial Proteins; Sirtuin 3; Sirtuins
PubMed: 35805129
DOI: 10.3390/cells11132045 -
Cellular Signalling Jun 2023Eukaryotic genomes are organised in a structure called chromatin, comprising of DNA and histone proteins. Chromatin is thus a fundamental regulator of gene expression,... (Review)
Review
Eukaryotic genomes are organised in a structure called chromatin, comprising of DNA and histone proteins. Chromatin is thus a fundamental regulator of gene expression, as it offers storage and protection but also controls accessibility to DNA. Sensing and responding to reductions in oxygen availability (hypoxia) have recognised importance in both physiological and pathological processes in multicellular organisms. One of the main mechanisms controlling these responses is control of gene expression. Recent findings in the field of hypoxia have highlighted how oxygen and chromatin are intricately linked. This review will focus on mechanisms controlling chromatin in hypoxia, including chromatin regulators such as histone modifications and chromatin remodellers. It will also highlight how these are integrated with hypoxia inducible factors and the knowledge gaps that persist.
Topics: Humans; Chromatin; Histones; Hypoxia; Oxygen; Protein Processing, Post-Translational; Acetylation
PubMed: 36990334
DOI: 10.1016/j.cellsig.2023.110660 -
Autophagy Dec 2021Aberrant chaperone-mediated autophagy (CMA) activation has been suggested as a tumorigenesis-promoting event in various cancers, although its roles in prostate cancer...
Aberrant chaperone-mediated autophagy (CMA) activation has been suggested as a tumorigenesis-promoting event in various cancers, although its roles in prostate cancer (PCa) remain elusive. Emerging evidence indicates that , a prostate-specific and androgen-responsive gene, contributes to the malignant progression of PCa. Here, we demonstrate that TPD52 enhances CMA activation by interacting with HSPA8/HSC70 and enhancing substrate degradation in PCa. Elevation of TPD52 is essential for CMA-induced PCa cell proliferation and stress resistance and . Furthermore, TPD52 is acetylated by KAT2B at K163, which is a process that can be antagonized by HDAC2. Inactivation of HDAC2 results in elevated TPD52 acetylation, which compromises the interaction between TPD52 and HSPA8, leading to impaired CMA function and tumor growth . Taken together, our findings reveal that acetylation-dependent regulation of TPD52 modulates CMA oncogenic function in PCa, thereby suggesting the possibility of targeting the TPD52-mediated CMA pathway to control the progression of PCa.: CMA: chaperone-mediated autophagy; HDAC2: histone deacetylase 2; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KAT2B: lysine acetyltransferase 2B; LAMP2A: lysosomal associated membrane protein 2A; PCa: prostate cancer; TPD52: tumor protein D52.
Topics: Acetylation; Autophagy; Chaperone-Mediated Autophagy; Humans; Lysosomal-Associated Membrane Protein 2; Lysosomes; Male; Neoplasm Proteins; Prostatic Neoplasms; Protein Isoforms
PubMed: 34034634
DOI: 10.1080/15548627.2021.1917130 -
Cell Communication and Signaling : CCS Feb 2024The phenomenon of phase separation is quite common in cells, and it is involved in multiple processes of life activities. However, the current research on the... (Review)
Review
The phenomenon of phase separation is quite common in cells, and it is involved in multiple processes of life activities. However, the current research on the correlation between protein modifications and phase separation and the interference with the tendency of phase separation has some limitations. Here we focus on several post-translational modifications of proteins, including protein phosphorylation modification at multiple sites, methylation modification, acetylation modification, ubiquitination modification, SUMOylation modification, etc., which regulate the formation of phase separation and the stability of phase separation structure through multivalent interactions. This regulatory role is closely related to the development of neurodegenerative diseases, tumors, viral infections, and other diseases, and also plays essential functions in environmental stress, DNA damage repair, transcriptional regulation, signal transduction, and cell homeostasis of living organisms, which provides an idea to explore the interaction between novel protein post-translational modifications and phase separation. Video Abstract.
Topics: Phase Separation; Protein Processing, Post-Translational; Ubiquitination; Phosphorylation; Proteins; Acetylation
PubMed: 38347544
DOI: 10.1186/s12964-023-01380-1 -
Clinical Epigenetics Jul 2019Peptides originating from different sources (endogenous, food derived, environmental, and synthetic) are able to influence different aspects of epigenetic regulation.... (Review)
Review
Peptides originating from different sources (endogenous, food derived, environmental, and synthetic) are able to influence different aspects of epigenetic regulation. Endogenous short peptides, resulting from proteolytic cleavage of proteins or upon translation of non-annotated out of frame transcripts, can block DNA methylation and hereby regulate gene expression. Peptides entering the body by digestion of food-related proteins can modulate DNA methylation and/or histone acetylation while environmental peptides, synthesized by bacteria, fungi, and marine sponges, mainly inhibit histone deacetylation. In addition, synthetic peptides that reverse or inhibit different epigenetic modifications of both histones and the DNA can be developed as well. Next to these DNA and histone modifications, peptides can also influence the expression of non-coding RNAs such as lncRNAs and the maturation of miRNAs.Seen the advantages over small molecules, the development of peptide therapeutics is an interesting approach to treat diseases with a strong epigenetic basis like cancer and Alzheimer's disease. To date, only a limited number of drugs with a proven epigenetic mechanism of action have been approved by the FDA of which two (romidepsin and nesiritide) are peptides. A large knowledge gap concerning epigenetic effects of peptides is present, and this class of molecules deserves more attention in the development as epigenetic modulators. In addition, none of the currently approved peptide drugs are under investigation for their potential effects on epigenetics, hampering drug repositioning of these peptides to other indications with an epigenetic etiology.
Topics: Acetylation; DNA Methylation; Epigenesis, Genetic; Histones; Humans; Peptides
PubMed: 31300053
DOI: 10.1186/s13148-019-0700-7