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Protein & Cell Dec 2022Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence... (Review)
Review
Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.
Topics: Chromatin; DNA Methylation; Epigenesis, Genetic; Epigenomics; Histones; Humans; Neoplasms
PubMed: 34050894
DOI: 10.1007/s13238-021-00846-7 -
International Journal of Molecular... Apr 2018Systemic hypertension, which eventually results in heart failure, renal failure or stroke, is a common chronic human disorder that particularly affects elders. Although... (Review)
Review
Systemic hypertension, which eventually results in heart failure, renal failure or stroke, is a common chronic human disorder that particularly affects elders. Although many signaling pathways involved in the development of hypertension have been reported over the past decades, which has led to the implementation of a wide variety of anti-hypertensive therapies, one half of all hypertensive patients still do not have their blood pressure controlled. The frontier in understanding the molecular mechanisms underlying hypertension has now advanced to the level of epigenomics. Particularly, increasing evidence is emerging that DNA methylation and histone modifications play an important role in gene regulation and are involved in alteration of the phenotype and function of vascular cells in response to environmental stresses. This review seeks to highlight the recent advances in our knowledge of the epigenetic regulations and mechanisms of hypertension, focusing on the role of DNA methylation and histone modification in the vascular wall. A better understanding of the epigenomic regulation in the hypertensive vessel may lead to the identification of novel target molecules that, in turn, may lead to novel drug discoveries for the treatment of hypertension.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Epigenomics; Gene Regulatory Networks; Histone Code; Histones; Humans; Hypertension
PubMed: 29649151
DOI: 10.3390/ijms19041174 -
Cell Research Mar 2011Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of... (Review)
Review
Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place.
Topics: Chromatin; Heterochromatin; Histone Demethylases; Histones; Protein Processing, Post-Translational
PubMed: 21321607
DOI: 10.1038/cr.2011.22 -
Gut Microbes 2022The gastrointestinal tract is continuously exposed to trillions of commensal microbes, collectively termed the microbiota, which are environmental stimuli that can... (Review)
Review
The gastrointestinal tract is continuously exposed to trillions of commensal microbes, collectively termed the microbiota, which are environmental stimuli that can direct health and disease within the host. In addition to well-established bacterial sensing pathways, microbial signals are also integrated through epigenetic modifications that calibrate the transcriptional program of host cells without altering the underlying genetic code. Microbiota-sensitive epigenetic changes include modifications to the DNA or histones, as well as regulation of non-coding RNAs. While microbiota-sensitive epigenetic mechanisms have been described in both local intestinal cells and as well in peripheral tissues, further research is required to fully decipher the complex relationship between the host and microbiota. This Review highlights current understandings of epigenetic regulation by gut microbiota and important implications of these findings in guiding therapeutic approaches to prevent or combat diseases driven by impaired microbiota-host interactions.
Topics: Animals; Bacteria; Epigenesis, Genetic; Gastrointestinal Microbiome; Gastrointestinal Tract; Histones; Host Microbial Interactions; Humans
PubMed: 35000562
DOI: 10.1080/19490976.2021.2022407 -
Molecular Cell Nov 2012Histone lysine methylation has emerged as a critical player in the regulation of gene expression, cell cycle, genome stability, and nuclear architecture. Over the past... (Review)
Review
Histone lysine methylation has emerged as a critical player in the regulation of gene expression, cell cycle, genome stability, and nuclear architecture. Over the past decade, a tremendous amount of progress has led to the characterization of methyl modifications and the lysine methyltransferases (KMTs) and lysine demethylases (KDMs) that regulate them. Here, we review the discovery and characterization of the KMTs and KDMs and the methyl modifications they regulate. We discuss the localization of the KMTs and KDMs as well as the distribution of lysine methylation throughout the genome. We highlight how these data have shaped our view of lysine methylation as a key determinant of complex chromatin states. Finally, we discuss the regulation of KMTs and KDMs by proteasomal degradation, posttranscriptional mechanisms, and metabolic status. We propose key questions for the field and highlight areas that we predict will yield exciting discoveries in the years to come.
Topics: Animals; Histone Demethylases; Histone-Lysine N-Methyltransferase; Histones; Humans; Lysine; Methylation
PubMed: 23200123
DOI: 10.1016/j.molcel.2012.11.006 -
Trends in Genetics : TIG Feb 2022Epigenetic modifications occur on genomic DNA and histones to influence gene expression. More recently, the discovery that mRNA undergoes similar chemical modifications... (Review)
Review
Epigenetic modifications occur on genomic DNA and histones to influence gene expression. More recently, the discovery that mRNA undergoes similar chemical modifications that powerfully impact transcript turnover and translation adds another layer of dynamic gene regulation. Central to precise and synchronized regulation of gene expression is intricate crosstalk between multiple checkpoints involved in transcript biosynthesis and processing. There are more than 100 internal modifications of RNA in mammalian cells. The most common is N-methyladenosine (mA) methylation. Although mA is established to influence RNA stability dynamics and translation efficiency, rapidly accumulating evidence shows significant crosstalk between RNA methylation and histone/DNA epigenetic mechanisms. These interactions specify transcriptional outputs, translation, recruitment of chromatin modifiers, as well as the deployment of the mA methyltransferase complex (MTC) at target sites. In this review, we dissect mA-orchestrated feedback circuits that regulate histone modifications and the activity of regulatory RNAs, such as long noncoding (lnc)RNA and chromosome-associated regulatory RNA. Collectively, this body of evidence suggests that mA acts as a versatile checkpoint that can couple different layers of gene regulation with one another.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Histones; Methylation; RNA, Long Noncoding
PubMed: 34294427
DOI: 10.1016/j.tig.2021.06.014 -
International Journal of Molecular... Aug 2020Histone H1 is the most variable histone and its role at the epigenetic level is less characterized than that of core histones. In vertebrates, H1 is a multigene family,... (Review)
Review
Histone H1 is the most variable histone and its role at the epigenetic level is less characterized than that of core histones. In vertebrates, H1 is a multigene family, which can encode up to 11 subtypes. The H1 subtype composition is different among cell types during the cell cycle and differentiation. Mass spectrometry-based proteomics has added a new layer of complexity with the identification of a large number of post-translational modifications (PTMs) in H1. In this review, we summarize histone H1 PTMs from lower eukaryotes to humans, with a particular focus on mammalian PTMs. Special emphasis is made on PTMs, whose molecular function has been described. Post-translational modifications in H1 have been associated with the regulation of chromatin structure during the cell cycle as well as transcriptional activation, DNA damage response, and cellular differentiation. Additionally, PTMs in histone H1 that have been linked to diseases such as cancer, autoimmune disorders, and viral infection are examined. Future perspectives and challenges in the profiling of histone H1 PTMs are also discussed.
Topics: Animals; Chromatin Assembly and Disassembly; Histone Code; Histones; Humans; Protein Processing, Post-Translational
PubMed: 32824860
DOI: 10.3390/ijms21165941 -
Cell Sep 2011We report the identification of 67 previously undescribed histone modifications, increasing the current number of known histone marks by about 70%. We further...
We report the identification of 67 previously undescribed histone modifications, increasing the current number of known histone marks by about 70%. We further investigated one of the marks, lysine crotonylation (Kcr), confirming that it represents an evolutionarily-conserved histone posttranslational modification. The unique structure and genomic localization of histone Kcr suggest that it is mechanistically and functionally different from histone lysine acetylation (Kac). Specifically, in both human somatic and mouse male germ cell genomes, histone Kcr marks either active promoters or potential enhancers. In male germinal cells immediately following meiosis, Kcr is enriched on sex chromosomes and specifically marks testis-specific genes, including a significant proportion of X-linked genes that escape sex chromosome inactivation in haploid cells. These results therefore dramatically extend the repertoire of histone PTM sites and designate Kcr as a specific mark of active sex chromosome-linked genes in postmeiotic male germ cells.
Topics: Animals; Gene Expression Regulation; HeLa Cells; Histone Code; Histones; Humans; Lysine; Male; Meiosis; Mice; Protein Processing, Post-Translational; Testis
PubMed: 21925322
DOI: 10.1016/j.cell.2011.08.008 -
Cell Mar 2023Chromatin landscapes are disrupted during DNA replication and must be restored faithfully to maintain genome regulation and cell identity. The histone H3-H4 modification...
Chromatin landscapes are disrupted during DNA replication and must be restored faithfully to maintain genome regulation and cell identity. The histone H3-H4 modification landscape is restored by parental histone recycling and modification of new histones. How DNA replication impacts on histone H2A-H2B is currently unknown. Here, we measure H2A-H2B modifications and H2A.Z during DNA replication and across the cell cycle using quantitative genomics. We show that H2AK119ub1, H2BK120ub1, and H2A.Z are recycled accurately during DNA replication. Modified H2A-H2B are segregated symmetrically to daughter strands via POLA1 on the lagging strand, but independent of H3-H4 recycling. Post-replication, H2A-H2B modification and variant landscapes are quickly restored, and H2AK119ub1 guides accurate restoration of H3K27me3. This work reveals epigenetic transmission of parental H2A-H2B during DNA replication and identifies cross talk between H3-H4 and H2A-H2B modifications in epigenome propagation. We propose that rapid short-term memory of recycled H2A-H2B modifications facilitates restoration of stable H3-H4 chromatin states.
Topics: Cell Cycle; Chromatin; DNA Replication; Histones; Memory, Short-Term; Nucleosomes; Animals; Mice; Rabbits
PubMed: 36750094
DOI: 10.1016/j.cell.2023.01.007 -
Trends in Genetics : TIG Jun 2021Complex mechanisms are in place to maintain genome stability. Ubiquitination of chromatin plays a central role in these mechanisms. The ever-growing complexity of the... (Review)
Review
Complex mechanisms are in place to maintain genome stability. Ubiquitination of chromatin plays a central role in these mechanisms. The ever-growing complexity of the ubiquitin (Ub) code and of chromatin modifications and dynamics challenges our ability to fully understand how histone ubiquitination regulates genome stability. Here we review the current knowledge on specific, low-abundant histone ubiquitination events that are highly regulated within the cellular DNA damage response (DDR), with particular emphasis on the latest discovery of Ub phosphorylation as a novel regulator of the DDR signaling pathway. We discuss players involved and potential implications of histone (phospho)ubiquitination on chromatin structure, and we highlight exciting open questions for future research.
Topics: Animals; DNA Damage; DNA Repair; Genomic Instability; Histones; Humans; Methylation; Phosphorylation; Ubiquitin; Ubiquitination
PubMed: 33485674
DOI: 10.1016/j.tig.2020.12.005