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The Journal of Biological Chemistry Apr 2023Plant homeodomain (PHD) fingers are structurally conserved zinc fingers that selectively bind unmodified or methylated at lysine 4 histone H3 tails. This binding... (Review)
Review
Plant homeodomain (PHD) fingers are structurally conserved zinc fingers that selectively bind unmodified or methylated at lysine 4 histone H3 tails. This binding stabilizes transcription factors and chromatin-modifying proteins at specific genomic sites, which is required for vital cellular processes, including gene expression and DNA repair. Several PHD fingers have recently been shown to recognize other regions of H3 or histone H4. In this review, we detail molecular mechanisms and structural features of the noncanonical histone recognition, discuss biological implications of the atypical interactions, highlight therapeutic potential of PHD fingers, and compare inhibition strategies.
Topics: DNA-Binding Proteins; Histones; PHD Zinc Fingers; Protein Binding; Transcription Factors; Animals; Mice; Neoplasms
PubMed: 36907441
DOI: 10.1016/j.jbc.2023.104601 -
Cold Spring Harbor Perspectives in... Jul 2016DNA and histone modifications, together with constraints imposed by nuclear architecture, contribute to the transcriptional regulatory landscape of the nervous system.... (Review)
Review
DNA and histone modifications, together with constraints imposed by nuclear architecture, contribute to the transcriptional regulatory landscape of the nervous system. Here, we provide select examples showing how these regulatory layers, often referred to as epigenetic, contribute to neuronal differentiation and function. We describe the interplay between DNA methylation and Polycomb-mediated repression during neuronal differentiation, the role of DNA methylation and long-range enhancer-promoter interactions in Protocadherin promoter choice, and the contribution of heterochromatic silencing and nuclear organization in singular olfactory receptor expression. Finally, we explain how the activity-dependent expression of a histone variant determines the longevity of olfactory sensory neurons.
Topics: DNA; DNA Methylation; Epigenesis, Genetic; Histones; Neurons; Promoter Regions, Genetic
PubMed: 27371659
DOI: 10.1101/cshperspect.a024208 -
Clinical Epigenetics Oct 2021Histone modification is an important form of epigenetic regulation. Thereinto, histone methylation is a critical determination of chromatin states, participating in... (Review)
Review
Histone modification is an important form of epigenetic regulation. Thereinto, histone methylation is a critical determination of chromatin states, participating in multiple cellular processes. As a conserved histone methylation mark, histone 3 lysine 36 trimethylation (H3K36me3) can mediate multiple transcriptional-related events, such as the regulation of transcriptional activity, transcription elongation, pre-mRNA alternative splicing, and RNA mA methylation. Additionally, H3K36me3 also contributes to DNA damage repair. Given the crucial function of H3K36me3 in genome regulation, the roles of H3K36me3 and its sole methyltransferase SETD2 in pathogenesis, especially malignancies, have been emphasized in many studies, and it is conceivable that disruption of histone methylation regulatory network composed of "writer", "eraser", "reader", and the mutation of H3K36me3 codes have the capacity of powerfully modulating cancer initiation and development. Here we review H3K36me3-mediated biological processes and summarize the latest findings regarding its role in cancers. We highlight the significance of epigenetic combination therapies in cancers.
Topics: DNA Methylation; Epigenesis, Genetic; Histones; Humans; Neoplasms
PubMed: 34715919
DOI: 10.1186/s13148-021-01187-2 -
Epigenetics & Chromatin Jan 2019Epigenetic modifications such as histone methylation permit change in chromatin structure without accompanying change in the underlying genomic sequence. A number of... (Review)
Review
Epigenetic modifications such as histone methylation permit change in chromatin structure without accompanying change in the underlying genomic sequence. A number of studies in animal models have shown that dysregulation of various components of the epigenetic machinery causes cognitive deficits at the behavioral level, suggesting that proper epigenetic control is necessary for the fundamental processes of learning and memory. Histone H3 lysine K4 (H3K4) methylation comprises one component of such epigenetic control, and global levels of this mark are increased in the hippocampus during memory formation. Modifiers of H3K4 methylation are needed for memory formation, shown through animal studies, and many of the same modifiers are mutated in human cognitive diseases. Indeed, all of the known H3K4 methyltransferases and four of the known six H3K4 demethylases have been associated with impaired cognition in a neurologic or psychiatric disorder. Cognitive impairment in such patients often manifests as intellectual disability, consistent with a role for H3K4 methylation in learning and memory. As a modification quintessentially, but not exclusively, associated with transcriptional activity, H3K4 methylation provides unique insights into the regulatory complexity of writing, reading, and erasing chromatin marks within an activated neuron. The following review will discuss H3K4 methylation and connect it to transcriptional events required for learning and memory within the developed nervous system. This will include an initial discussion of the most recent advances in the developing methodology to analyze H3K4 methylation, namely mass spectrometry and deep sequencing, as well as how these methods can be applied to more deeply understand the biology of this mark in the brain. We will then introduce the core enzymatic machinery mediating addition and removal of H3K4 methylation marks and the resulting epigenetic signatures of these marks throughout the neuronal genome. We next foray into the brain, discussing changes in H3K4 methylation marks within the hippocampus during memory formation and retrieval, as well as the behavioral correlates of H3K4 methyltransferase deficiency in this region. Finally, we discuss the human cognitive diseases connected to each H3K4 methylation modulator and summarize advances in developing drugs to target them.
Topics: Animals; Cognition Disorders; Histone Code; Histones; Humans; Memory; Methylation
PubMed: 30616667
DOI: 10.1186/s13072-018-0251-8 -
DNA Repair Aug 2017DNA double strand breaks need to be repaired in an organized fashion to preserve genomic integrity. In the organization of faithful repair, histone ubiquitination plays... (Review)
Review
DNA double strand breaks need to be repaired in an organized fashion to preserve genomic integrity. In the organization of faithful repair, histone ubiquitination plays a crucial role. Recent findings suggest an integrated model for DNA repair regulation through site-specific histone ubiquitination and crosstalk to other posttranslational modifications. Here we discuss how site-specific histone ubiquitination is achieved on a molecular level and how different multi-protein complexes work together to integrate different histone ubiquitination states. We propose a model where site-specific H2A ubiquitination organizes the spatio-temporal recruitment of DNA repair factors which will ultimately contribute to DNA repair pathway choice between homologous recombination and non-homologous end joining.
Topics: Animals; DNA; DNA Breaks, Double-Stranded; DNA End-Joining Repair; Histones; Humans; Recombinational DNA Repair; Signal Transduction; Ubiquitination
PubMed: 28624371
DOI: 10.1016/j.dnarep.2017.06.011 -
ACS Chemical Biology Mar 2016Histones are subject to frequent combinatorial post-translational modifications (PTMs), forming a complex chemical "language" that is interpreted by PTM-specific... (Review)
Review
Histones are subject to frequent combinatorial post-translational modifications (PTMs), forming a complex chemical "language" that is interpreted by PTM-specific histone-interacting protein modules (reader domains). These specific interactions are thought to instruct gene expression and downstream biological functions. While the majority of studies have focused on individual modifications, our current understanding of the combinatorial PTM patterns on histones is starting to emerge, benefiting from the convergence of multiple technologies. Here, we review the key technical advances and progress on discovery and characterization of combinatorial histone PTM patterns. We focus on the interactions between reader domains and combinatorial PTMs, which is essential for understanding the mechanism and biological meaning of establishing and interpreting information embedded in histone PTM patterns.
Topics: Chromatin; Epigenesis, Genetic; Histones; Humans; Protein Domains; Protein Processing, Post-Translational
PubMed: 26675328
DOI: 10.1021/acschembio.5b00864 -
Biochimica Et Biophysica Acta 2012Histone acetyltransferase 1 (HAT1) is an enzyme that is likely to be responsible for the acetylation that occurs on lysines 5 and 12 of the NH2-terminal tail of newly... (Review)
Review
Histone acetyltransferase 1 (HAT1) is an enzyme that is likely to be responsible for the acetylation that occurs on lysines 5 and 12 of the NH2-terminal tail of newly synthesized histone H4. Initial studies suggested that, despite its evolutionary conservation, this modification of new histone H4 played only a minor role in chromatin assembly. However, a number of recent studies have brought into focus the important role of both this modification and HAT1 in histone dynamics. Surprisingly, the function of HAT1 in chromatin assembly may extend beyond just its catalytic activity to include its role as a major histone binding protein. These results are incorporated into a model for the function of HAT1 in histone deposition and chromatin assembly. This article is part of a Special issue entitled: Histone chaperones and Chromatin assembly.
Topics: Acetylation; Animals; Chromatin Assembly and Disassembly; Histone Acetyltransferases; Histones; Humans; Protein Binding; Protein Structure, Tertiary
PubMed: 24459728
DOI: 10.1016/j.bbagrm.2011.07.006 -
Brazilian Journal of Biology = Revista... 2022Valproic acid in association with sodium valproate (VPA) is an important anticonvulsant drug used for decades to treat neurological disorders. VPA also acts as an... (Review)
Review
Valproic acid in association with sodium valproate (VPA) is an important anticonvulsant drug used for decades to treat neurological disorders. VPA also acts as an epigenetic modulator by inhibiting histone deacetylases, permitting histone acetylation, affecting the DNA and histone methylation status and gene expression, and inducing chromatin remodeling. Insects represent an important animal model for studies in several areas of science. Their high phenotypic plasticity makes them alternative models for epigenetic studies. This brief review emphasizes recent reports on insect epigenetics and the contribution of studies on the VPA action in insects, including effects on epigenetic markers, extending the pharmacological understanding of the potential of this drug, and demonstrating the usefulness of insects as an alternative animal model to drug studies.
Topics: Acetylation; Animals; Disease Models, Animal; Epigenesis, Genetic; Histones; Insecta; Valproic Acid
PubMed: 35416850
DOI: 10.1590/1519-6984.256045 -
Postepy Biochemii Oct 2018Gene expression of both normal and cancer cell is tightly regulated by specific transcription regulators and epigenetic mechanisms such as DNA methylation, histone... (Review)
Review
Gene expression of both normal and cancer cell is tightly regulated by specific transcription regulators and epigenetic mechanisms such as DNA methylation, histone modifications (acetylation, methylation, phosphorylation), nucleosome remodeling and non-coding RNAs. Deregulation of epigenetic mechanisms plays a pivotal role in cancer, although researchers debate if it is a cause or a consequence of oncogenic transformation. Independently from the way in which epigenetic alterations arise in cancer, downstream effects will result in profound changes in transcriptomic and subsequently proteomic profiles. In most cases, changes in expression of epigenetic genes produce functional advantages in cell proliferation, tumor growth and/or migration capacity. Most of epigenetic changes in cancer are triggered by genomic alterations in specific genes that are involved in controlling one of the epigenetic mechanisms. However, there are also mutations in cell metabolism-related genes that affect activities of DNA demethylating enzymes and histone modifiers. Histone modifications are deregulated in cancer mostly due to alterations in genes coding for enzymes that attach or remove histone modifications. Mutations in genes coding for nucleosome remodelers result in aberrant global chromatin organization and facilitate subsequent global alterations of gene copy number or translocations. Recent advancements in next generation sequencing allowed for more precise mapping of global changes in the epigenetic landscape in cancer.
Topics: DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histones; Humans; Neoplasms; Proteomics
PubMed: 30656897
DOI: 10.18388/pb.2018_125 -
BioEssays : News and Reviews in... Jan 2015We propose for the first time to divide histone proteolysis into "histone degradation" and the epigenetically connoted "histone clipping". Our initial observation is... (Review)
Review
We propose for the first time to divide histone proteolysis into "histone degradation" and the epigenetically connoted "histone clipping". Our initial observation is that these two different classes are very hard to distinguish both experimentally and biologically, because they can both be mediated by the same enzymes. Since the first report decades ago, proteolysis has been found in a broad spectrum of eukaryotic organisms. However, the authors often not clearly distinguish or determine whether degradation or clipping was studied. Given the importance of histone modifications in epigenetic regulation we further elaborate on the different ways in which histone proteolysis could play a role in epigenetics. Finally, unanticipated histone proteolysis has probably left a mark on many studies of histones in the past. In conclusion, we emphasize the significance of reviving the study of histone proteolysis both from a biological and an experimental perspective. Also watch the Video Abstract.
Topics: Animals; Histones; Humans; Models, Biological; Proteolysis
PubMed: 25350939
DOI: 10.1002/bies.201400118