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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 -
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 -
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 -
EMBO Reports Feb 2021Lysine succinylation (Ksucc) is an evolutionarily conserved and widespread post-translational modification. Histone acetyltransferase 1 (HAT1) is a type B histone...
Lysine succinylation (Ksucc) is an evolutionarily conserved and widespread post-translational modification. Histone acetyltransferase 1 (HAT1) is a type B histone acetyltransferase, regulating the acetylation of both histone and non-histone proteins. However, the role of HAT1 in succinylation modulation remains unclear. Here, we employ a quantitative proteomics approach to study succinylation in HepG2 cancer cells and find that HAT1 modulates lysine succinylation on various proteins including histones and non-histones. HAT1 succinylates histone H3 on K122, contributing to epigenetic regulation and gene expression in cancer cells. Moreover, HAT1 catalyzes the succinylation of PGAM1 on K99, resulting in its increased enzymatic activity and the stimulation of glycolytic flux in cancer cells. Clinically, HAT1 is significantly elevated in liver cancer, pancreatic cancer, and cholangiocarcinoma tissues. Functionally, HAT1 succinyltransferase activity and the succinylation of PGAM1 by HAT1 play critical roles in promoting tumor progression in vitro and in vivo. Thus, we conclude that HAT1 is a succinyltransferase for histones and non-histones in tumorigenesis.
Topics: Acetylation; Carcinogenesis; Epigenesis, Genetic; Hep G2 Cells; Histone Acetyltransferases; Histones; Humans
PubMed: 33372411
DOI: 10.15252/embr.202050967 -
Nature Communications Jun 2023Faithful inheritance of parental histones is essential to maintain epigenetic information and cellular identity during cell division. Parental histones are evenly...
Faithful inheritance of parental histones is essential to maintain epigenetic information and cellular identity during cell division. Parental histones are evenly deposited onto the replicating DNA of sister chromatids in a process dependent on the MCM2 subunit of DNA helicase. However, the impact of aberrant parental histone partition on human disease such as cancer is largely unknown. In this study, we construct a model of impaired histone inheritance by introducing MCM2-2A mutation (defective in parental histone binding) in MCF-7 breast cancer cells. The resulting impaired histone inheritance reprograms the histone modification landscapes of progeny cells, especially the repressive histone mark H3K27me3. Lower H3K27me3 levels derepress the expression of genes associated with development, cell proliferation, and epithelial to mesenchymal transition. These epigenetic changes confer fitness advantages to some newly emerged subclones and consequently promote tumor growth and metastasis after orthotopic implantation. In summary, our results indicate that impaired inheritance of parental histones can drive tumor progression.
Topics: Humans; Histones; Epithelial-Mesenchymal Transition; Epigenesis, Genetic; DNA Helicases; Histone Code
PubMed: 37301892
DOI: 10.1038/s41467-023-39185-y -
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 -
Epigenetics & Chromatin Feb 2021Histone crotonylation is a recently described post-translational modification that occurs at multiple identified histone lysine crotonylation sites. An increasing number... (Review)
Review
Histone crotonylation is a recently described post-translational modification that occurs at multiple identified histone lysine crotonylation sites. An increasing number of studies have demonstrated that histone crotonylation at DNA regulatory elements plays an important role in the activation of gene transcription. However, among others, we have shown that elevated cellular crotonylation levels result in the inhibition of endocytosis-related gene expression and pro-growth gene expression, implicating the complexity of histone crotonylation in gene regulation. Therefore, it is important to understand how histone crotonylation is regulated and how it, in turn, regulates the expression of its target genes. In this review, we summarize the regulatory factors that control histone crotonylation and discuss the role of different histone crotonylation sites in regulating gene expression, while providing novel insights into the central role of histone crotonylation in gene regulation.
Topics: Gene Expression Regulation; Histones; Lysine; Protein Processing, Post-Translational
PubMed: 33549150
DOI: 10.1186/s13072-021-00385-9 -
Genome Apr 2021Canonical histones (H2A, H2B, H3, and H4) are present in all eukaryotes where they package genomic DNA and participate in numerous cellular processes, such as... (Review)
Review
Canonical histones (H2A, H2B, H3, and H4) are present in all eukaryotes where they package genomic DNA and participate in numerous cellular processes, such as transcription regulation and DNA repair. In addition to the canonical histones, there are many histone variants, which have different amino acid sequences, possess tissue-specific expression profiles, and function distinctly from the canonical counterparts. A number of histone variants, including both core histones (H2A/H2B/H3/H4) and linker histones (H1/H5), have been identified to date. Htz1 (H2A.Z) and CENP-A (CenH3) are present from yeasts to mammals, and H3.3 is present from to humans. In addition to the prevalent variants, others like H3.4 (H3t), H2A.Bbd, and TH2B, as well as several H1 variants, are found to be specific to mammals. Among them, H2BFWT, H3.5, H3.X, H3.Y, and H4G are unique to primates (or Hominidae). In this review, we focus on localization and function of primate- or hominidae-specific histone variants.
Topics: Amino Acid Sequence; Animals; Brain; Breast Neoplasms; Cell Nucleolus; DNA; Gene Expression Regulation; Histones; Humans; Mammals; Phylogeny; Primates
PubMed: 33245240
DOI: 10.1139/gen-2020-0094 -
Cell Research Mar 2011"Epigenetics" is currently defined as "the inheritance of variation (-genetics) above and beyond (epi-) changes in the DNA sequence". Despite the fact that histones are... (Review)
Review
"Epigenetics" is currently defined as "the inheritance of variation (-genetics) above and beyond (epi-) changes in the DNA sequence". Despite the fact that histones are believed to carry important epigenetic information, little is known about the molecular mechanisms of the inheritance of histone-based epigenetic information, including histone modifications and histone variants. Here we review recent progress and discuss potential models for the mitotic inheritance of histone modifications-based epigenetic information.
Topics: Epigenesis, Genetic; Histones; Methylation; Mitosis; Models, Genetic
PubMed: 21321606
DOI: 10.1038/cr.2011.26 -
Current Topics in Medicinal Chemistry 2016Acetylation is an important, reversible post-translational modification affecting histone and non-histone proteins with critical roles in gene transcription, DNA... (Review)
Review
Acetylation is an important, reversible post-translational modification affecting histone and non-histone proteins with critical roles in gene transcription, DNA replication, DNA repair, and cell cycle progression. Key regulatory enzymes include histone deacetylase (HDACs) and histone acetyltransferases (HATs). Overexpressed HDACs have been identified in many human cancers, resulting in repressed chromatin states that interfere with vital tumor suppressor functions. Inhibition of HDAC activity has been pursued as a mechanism for re-activating repressed genes in cancers, with some HDAC inhibitors showing promise in the clinical setting. Dietary compounds and their metabolites also have been shown to modulate HDAC activity or expression. Out of this body of research, attention increasingly has shifted towards non-histone targets of HDACs and HATs, such as transcriptions factors, hormone receptors, DNA repair proteins, and cytoskeletal components. These aspects are covered in present review, along with the possible clinical significance. Where such data are available, examples are cited from the literature of studies with short chain fatty acids, polyphenols, isoflavones, indoles, organosulfur compounds, organoselenium compounds, sesquiterpene lactones, isoflavones, and various miscellaneous agents. By virtue of their effects on both histone and non-histone proteins, dietary chemopreventive agents modulate the cellular acetylome in ways that are only now becoming apparent. A better understanding of the molecular mechanisms will likely enhance the potential to more effectively combat diseases harboring altered epigenetic landscapes and dysregulated protein signaling.
Topics: Acetylation; Animals; Biological Products; Diet; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Histones; Humans
PubMed: 26303421
DOI: 10.2174/1568026615666150825125857