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PubMed2026

Diversity and evolution of chromatin regulatory states across eukaryotes.

Histone post-translational modifications (hPTMs) are key regulators of chromatin states, influencing gene expression, epigenetic memory and transposable element repression across eukaryotic genomes. While many hPTMs are evolutionarily conserved, the extent to which the chromatin states they define are similarly preserved remains unclear. Here we developed a combinatorial indexing chromatin immunoprecipitation followed by sequencing method to simultaneously profile specific hPTMs across diverse eukaryotic lineages, including amoebozoans, rhizarians, discobans and cryptomonads. Our analyses revealed highly conserved euchromatin states at active gene promoters and gene bodies. In contrast, we observed diverse configurations of repressive heterochromatin states associated with silenced genes and transposable elements, characterized by various combinations of hPTMs such as H3K9me3, H3K27me3 and/or different H3K79 methylations. These findings suggest that, while core hPTMs are ancient and broadly conserved, their functional readout has diversified throughout eukaryotic evolution, shaping lineage-specific chromatin landscapes.

Histones↗
PubMed2005

Histone H2A phosphorylation in DNA double-strand break repair.

DNA repair must take place within the context of chromatin, and it is therefore not surprising that many aspects of both chromatin components and proteins that modify chromatin have been implicated in this process. One of the best-characterized chromatin modification events in DNA-damage responses is the phosphorylation of the SQ motif found in histone H2A or the H2AX histone variant in higher eukaryotes. This modification is an early response to the induction of DNA damage, and occurs in a wide range of eukaryotic organisms, suggesting an important conserved function. One function that histone modifications can have is to provide a unique binding site for interacting factors. Here, we review the proteins and protein complexes that have been identified as H2AS129ph (budding yeast) or H2AXS139ph (human) binding partners and discuss the implications of these interactions.

Animals↗
PubMed2004

Immunohistochemical detection of acetylation and phosphorylation of histone H3 in cervical smears.

OBJECTIVE: Histones bind in a sequence-independent manner to form chromatin. The aminoterminal tails of histones are targets for both phosphorylation and acetylation events. These modifications are thought to fundamentally regulate chromatin structure to accommodate transcription, DNA replication, mitosis and DNA repair. Regeneration of squamous epithelium is accompanied by marked cellular atypia, nuclear and nucleolar pleomorphism which could be confused with neoplasia. The aim of the study was to detect phosphorylated and acetylated forms of histone H3 in cytological smears. DESIGN: Translational research. SETTING: Department of Experimental Oncology, Masaryk Memorial Cancer Institute, Department of Pathological Physiology, Medical Faculty and Department of Obstetrics and Gynecology, Masaryk University, Czech Republic. METHODS: Smears from women aged between 20 to 46 years were selected. The specimens comprised 10 squamous metaplasia, 20 CIN I, 12 CIN II, and 14 CIN III. The smears were stained with polyclonal antibodies against phosphorylated and acetylated forms of histone H3. RESULTS: We found that nuclear positivity for phosphorylated (P) and acetylated (A) forms of histone H3 in CIN II (23% P, 33% A) and CIN III (25% P, 44% A) was higher in comparison with CIN I (8% P, 15% A) and metaplasia (11% P, 12% A). CONCLUSION: We revealed a marked association of histone H3 modifications with the progression of CIN II, CIN III in comparison with CIN I and metaplasia. Our results are in agreement with recent findings: 1. staining of cells with anti-phospho-histone H3 antibodies therefore provides a highly specific marker for mitosis. 2. acetylation of nucleosomal histones correlates with localised transcriptional activity.

Acetylation↗
PubMed1999

Poly(ADP-ribosylation) protects maternally derived histones from proteolysis after fertilization.

Fertilization in sea urchins is followed by the replacement of sperm-specific histones by cleavage-stage histone variants recruited from maternal stores. Such remodelling of zygote chromatin involves a cysteine proteinase that degrades the sperm-specific histones in a selective manner, leaving the maternal cleavage-stage histone variants intact. The mechanism that determines the selectivity of the sperm-histone-selective proteinase (SpH-proteinase) was analysed by focusing on the post-translational modification status of both sets of histones. It has previously been reported that only native cleavage-stage histones are poly(ADP-ribosylated), whereas the sperm-specific histones are not modified. To determine whether the poly(ADP-ribose) moiety afforded protection from degradation, the ADP-ribose polymers were removed from the cleavage-stage histones in vitro; these proteins were then assayed as potential substrates of the SpH-proteinase. Strikingly, the cleavage-stage histone variants were extensively degraded after the enzymic removal of their ADP-ribose moieties. In addition, the SpH cysteine proteinase was not inhibited by isolated poly(ADP-ribose) polymers. Consequently, only poly(ADP-ribosylated) cleavage-stage histone variants are protected from proteolysis. These results demonstrate a novel role for this type of post-translational modification, namely the protection of nuclear proteins against nuclear proteinases after fertilization.

Animals↗
PubMed2005

The histone code at DNA breaks: a guide to repair?

Chromatin modifications are important for all cellular processes that involve DNA, including transcription, replication and DNA repair. Chromatin can be modified by the addition of adducts to histone tail residues or by nucleosome remodelling, which requires ATP-dependent chromatin-remodelling complexes. Although the role of these mechanisms in transcription is well studied, their impact on DNA repair has only recently become evident. One crucial chromatin modification, the phosphorylation of histone H2A, links the recruitment of histone modifiers and ATP-dependent chromatin-remodelling complexes to sites of DNA damage.

Adenosine Triphosphate↗
PubMed1991

Transcription-induced nucleosome 'splitting': an underlying structure for DNase I sensitive chromatin.

Utilizing yeast strains containing promoter mutations, we demonstrate that transcription of the HSP82 gene causes nucleosomes toward the 3'-end to become DNase I sensitive and 'split' into structures that exhibit a 'half-nucleosomal' cleavage periodicity. Splitting occurs even when only a few RNA polymerase II molecules are engaged in basal level transcription or during the first round of induced transcription. The split nucleosomal structure survives nuclear isolation suggesting that it may be stabilized by post-translational modifications or non-histone proteins, and may require DNA replication for reversal to a whole nucleosomal structure. Split nucleosomes represent a structure for DNase I sensitive chromatin and are probably of common occurrence but difficult to detect experimentally. We suggest that transient positive supercoils downstream of traversing RNA polymerase lead to nucleosome splitting.

Chromatin↗
PubMed1987

Regulation of the ubiquitin-mediated proteolytic pathway: role of the substrate alpha-NH2 group and of transfer RNA.

Degradation of intracellular proteins via the ubiquitin pathway involves several steps. In the initial event, ubiquitin becomes covalently linked to the protein substrate in an ATP-requiring reaction. Following ubiquitin conjugation, the protein moiety of the adduct is selectively degraded with the release of free and reusable ubiquitin. Ubiquitin modification of a variety of protein targets in the cell plays a role in basic cellular functions. Modification of core nucleosomal histones is probably involved in regulation of gene expression at the level of chromatin structure. Ubiquitin attachment to cell surface proteins may play roles in processes of cell-cell interaction and adhesion, and conjugation of ubiquitin to other yet to be identified protein(s) could be involved in the progression of cells through the cell cycle. Despite the considerable progress that has been made in the elucidation of the mode of action and cellular roles of the ubiquitin pathway, many major problems remain unsolved. A problem of central importance is the specificity in the ubiquitin ligation system. Why are certain proteins conjugated and committed for degradation, whereas other proteins are not? A free alpha-NH2 group is an important feature of the protein structure recognized by the ubiquitin conjugation system, and tRNA is required for the conjugation of ubiquitin to selective proteolytic substrates and for their subsequent degradation. These findings can shed light on some of the features of a substrate that render it susceptible to ubiquitin-mediated degradation.

Amines↗
PubMed2004

Signaling through monoubiquitination.

Ubiquitination is a post-translational modification in which a small conserved peptide, ubiquitin, is appended to target proteins in the cell, through a series of complex enzymatic reactions. Recently, a particular form of ubiquitination, monoubiquitination, has emerged as a nonproteolytic reversible modification that controls protein function. In this review, we highlight recent findings on monoubiquitination as a signaling-induced modification, controlled, among others, by pathways originating from active receptor tyrosine kinases. Furthermore, we review the major cellular processes controlled by ubiquitin modification, including membrane trafficking, histone function, transcription regulation, DNA repair, and DNA replication.

Animals↗
PubMed2006

Characterization of chromatin samples in the presence of Drosophila embryo extract by quantitative agarose gel electrophoresis.

Recent studies have focused attention on chromatin as both a negative and positive regulator of specific nuclear events. The vast majority of this research has been centered on chromatin remodeling and histone post-translational modifications over the regulatory regions of specific genes. However, due the technical difficulties of such studies, the contribution of the higher-order structure of chromatin on the regulation of gene expression has not been as thoroughly investigated and the majority of the initial studies have used biophysical methods or microscopy. Until recent technical developments, the main hindrance for these biophysical investigations of chromatin has been an almost absolute requirement for large amounts of highly purified material. The development of an agarose gel electrophoresis method (quantitative agarose gel electrophoresis), initially designed for the analysis of the three-dimensional structure of purified and in vivo-assembled chromatin over a promoter region, has been expanded to include studies of chromatin in the presence of a Drosophila crude extract. The technique presented in the study reported here will help in paving the way for subsequent analyses of structural modifications of chromatin that are linked with the recruitment of various chromatin-associated factors present in the provided extract(s).

Animals↗
PubMed2005

The human peroxisome proliferator-activated receptor delta gene is a primary target of 1alpha,25-dihydroxyvitamin D3 and its nuclear receptor.

Peroxisome proliferator-activated receptor (PPAR) delta is the most widely expressed member of the PPAR family of nuclear receptor fatty acid sensors. Real-time PCR analysis of breast and prostate cancer cell lines demonstrated that PPARdelta expression was increased 1.5 to 3.2-fold after three hours stimulation with the natural vitamin D receptor (VDR) agonist, 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3). In silico analysis of the 20 kb of the human PPARdelta promoter revealed a DR3-type 1alpha,25(OH)2D3 response element approximately 350 bp upstream of the transcription start site, which was able to bind VDR-retinoid X receptor (RXR) heterodimers and mediate a 1alpha,25(OH)2D3-dependent upregulation of reporter gene activity. Chromatin immuno-precipitation assays demonstrated that a number of proteins representative for 1alpha,25(OH)2D3-mediated gene activation, such as VDR, RXR and RNA polymerase II, displayed a 1alpha,25(OH)2D3-dependent association with a region of the proximal PPARdelta promoter that contained the putative DR3-type VDRE. This was also true for other proteins that are involved in or are the subject of chromatin modification, such as the histone acetyltransferase CBP and histone 4, which displayed ligand-dependent association and acetylation, respectively. Finally, real-time PCR analysis demonstrated that 1alpha,25(OH)2D3 and the synthetic PPARdelta ligand L783483 show a cell and time-dependent interference in each other's effects on VDR mRNA expression, so that their combined application shows complex effects on the induction of VDR target genes, such as CYP24. Taken together, we conclude that PPARdelta is a primary 1alpha,25(OH)2D3-responding gene and that VDR and PPARdelta signaling pathways are interconnected at the level of cross-regulation of their respective transcription factor mRNA levels.

Cell Line, Tumor↗
PubMed2006

Structure of the '30 nm' chromatin fibre: a key role for the linker histone.

The structure of the '30 nm' chromatin fibre has eluded us for 30 years and remains a major unsolved problem in biology. Progress during the past year has led to the proposal of two significantly different models: one derived from the crystal structure of a four-nucleosome core array lacking the linker histone and the other, much more compact structure, derived from electron microscopy analysis of long nucleosome arrays containing the linker histone. The first model is of the two-start helix type, the second a one-start helix with interdigitated nucleosomes. These models provide new evidence that the topology and compactness of the '30 nm' chromatin fibre structure are regulated by the linker histone. The structural information also provides insights into the mechanisms by which the degree of chromatin compaction might be regulated by histone composition and post-transcriptional modifications.

Chromatin↗
PubMed1998

Chromosomal imprinting in plants.

Chromosomal imprints in the broadest sense can arise in somatic as well as germline cells. They can be imposed through the modification of chromosomal proteins or by the modification of chromosomal DNA, and they typically effect the expression of nearby genes. Modification enzymes--such as histone deacetylases and cytosine methyltransferases, as well as chromatin components--are known to play this role in animals and many of these same enzymes and components have been found in plants. Transposable elements are subject to chromosomal imprinting and may play a fundamental role in this process in plant and other eukaryotic genomes.

Animals↗
PubMed2004

Zebularine: a candidate for epigenetic cancer therapy.

For many years, the search for cancer therapy targets focused on the genetic changes associated with the transformation of normal cells into malignant cells. However, it is now clear that disruptions in epigenetic mechanisms--modifications of DNA or histones that heritably alter gene expression without mutating DNA--are important in cancer. Zebularine is a stable DNA cytosine methylation inhibitor that is currently in development as an epigenetic therapy for cancer.

Antineoplastic Agents↗
PubMed2007

Weak interaction induces an ON/OFF switch, whereas strong interaction causes gradual change: folding transition of a long duplex DNA chain by poly-L-lysine.

A large-scale conformational change in genomic DNA is an essential feature of gene activation in living cells. Considerable effort has been applied to explain the mechanism in terms of key-lock interaction between sequence-specific regulatory proteins and DNA, in addition to the modification of DNA and histones such as methylation and acetylation. However, it is still unclear whether these mechanisms can explain the ON/OFF switching of a large number of genes that accompanies differentiation, carcinogenesis, etc. In this study, using single-molecule observation of DNA molecules by fluorescence microscopy with the addition of poly-L-lysine with different numbers of monomer units (n = 3, 5, 9, and 92), we found that an ON/OFF discrete transition in the higher-order structure of long duplex DNA is induced by short poly-L-lysine, whereas a continuous gradual change is induced by long poly-L-lysine. On the other hand, polycations with a lower positive charge have less potential to induce DNA compaction. Such a drastic difference in the conformational transition of a giant DNA between short and large oligomers is discussed in relation to the mechanisms of gene regulation in a living cell.

Biophysics↗
PubMed2005

Combination therapy with DNA methyltransferase inhibitors in hematologic malignancies.

A variety of epigenetic changes contribute to transcriptional dysregulation in myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML). DNA methyltransferase (DNMT) inhibitors--azacitidine and decitabine--have significant activity in the treatment of MDS. Despite marked activity in myeloid malignancy, monotherapy with DNMT inhibitors is limited by low complete and partial response rates (7-20%) and median response durations of 15 months. As with classical cytotoxic therapy, the targeting of biologic pathways and mechanisms may best be accomplished using a combination of agents offering complementary mechanisms and synergistic pharmacodynamic interactions. The goal of this approach is to improve response rates, quality, and duration, and to minimize adverse events. There are a number of new therapies under development for the management of MDS and AML. This review article touches on some of the more promising combination regimens in various phases of investigation. The treatment of MDS and AML is undergoing rapid evolution. Cytogenetic complete remission and prolonged survival represent important goals. Incremental improvements in disease state and quality-of-life issues are also important for patients. Given the overall failure of cytotoxic chemotherapy in the achievement of cures in MDS and MDS-related AML, the application of less toxic, biologically directed agents may represent a more promising approach to treatment. Combination therapies with DNMT inhibitors using optimal dosing regimens to focus on methylation reversal with lower doses over longer periods of time, rather than direct cytotoxic effects, are beginning to suggest promising results in MDS and AML.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2026

Metab8D: a metabolic regulome network from multiomics and machine learning.

To explore multiomic regulation of the metabolome, we used machine learning to predict metabolomic variation across ~1000 different cancer cell lines with matched omics data from eight biomolecular classes: genomic copy number variation, mutations, DNA methylation, histone post-translational modifications (PTMs), transcriptomics and RNA splice variants, non-coding transcriptomics (miRNA and lncRNA), proteomics, and phosphoproteomics. Overall, the metabolome is tightly associated with the transcriptome, with coding and non-coding RNAs emerging as top predictors. Peripheral metabolites are predictable via levels of corresponding enzymes, while those in central metabolism require combinatorial predictors in signaling and redox pathways, and may not reflect corresponding pathway expression. We reconstruct multiomic interaction subnetworks for highly predictable metabolites, and YAP1 signaling emerged as a top global predictor across four omic layers. We prioritize predictive multiomic features for single-cell and spatial metabolomics assays. Top predictors were enriched for synthetic-lethal interactions and synergistic combination therapies that target compensatory metabolic modulators.

Machine Learning↗
PubMed2002

MeCP2 and MBD2 expression during normal and pathological growth of the human mammary gland.

During the last years, a direct link between DNA methylation and repressive chromatin structure has been established. This structural modification is mediated by histone deacetylases targeted to the methylated sequences by Methyl Binding Proteins (MBD). Human cancer cells exhibit both a global hypomethylation and some localized hypermethylations suggesting that the deregulation of the methylation machinery is a central event in tumorigenesis. Therefore, we have investigated in human tissues the expression of two major MBDs, MeCP2 and MBD2, during the proliferation of normal breast and in benign and neoplasic breast tumors. Quantitation of the transcripts indicates that MBD2 mRNAs are 20-30-fold more abundant than MeCP2 transcripts in the adult and fetal human mammary gland. In pathological tissues samples MBD2 mRNA levels are significantly higher (P=0.001) in benign tumors compared with normal breast tissues, whereas MeCP2 expression is not modified in these specimens. In neoplasic samples a deregulation of the expression of both genes was found. The amounts of MBD2 and MeCP2 transcripts vary greatly between samples in cancer cells compared to normal breast tissues or benign tumors, and in invasive ductal carcinomas the amount of MBD2 mRNA is significantly (P=0.03) associated with the tumor size. Taken together these data suggest that upregulation of MBD2 might be associated with breast cell proliferation. In line with this hypothesis MBD2 is also upregulated during the prenatal development of the human mammary gland, but in contrast to that observed in tumor cells, MeCP2 is also coordinately upregulated in the fetal breast tissues, suggesting that deregulation of MeCP2 and MBD2 occurs in human breast cancers.

Blotting, Western↗
PubMed1995

Histone nuclear proteins are irreversibly modified by reactive metabolites of diethylstilbestrol.

We demonstrate for the first time that diethylstilbestrol (DES), a synthetic estrogen, is converted by nuclei to histone-binding metabolite(s). Reaction of [3H]DES with nuclei in the presence of cumene hydroperoxide or NADPH revealed binding of [3H]DES to histone nuclear proteins. Gel electrophoresis experiments revealed that all five histones, 1, 2A, 2B, 3, and 4, were irreversibly bound to [3H]DES. Histones 1 and 3 were more susceptible to the attack by [3H]DES quinone, a metabolite of DES, than histones 2A, 2B, or 4. The kinetic constants, Km and Vmax, of this binding reaction in the presence of cumene hydroperoxide were 10 microM and 750 pmol/mg protein/30 min, respectively. This binding was significantly inhibited by cytochromes P-450 inhibitors. Low-molecular-weight thiols, such as glutathione and cysteine, or thiol modifiers, such as n-ethylmaleimide, dithionitrobenzoic acid, and hydroxymercuric benzoate, drastically inhibited binding of [3H]DES quinone to histone 3. The binding of [3H]DES metabolites to both transcriptionally active and inactive chromatin histone proteins was observed. We conclude that DES is metabolized to histone-binding metabolites, presumably by nuclear cytochrome P-450. DES quinone may be one of the histone-binding DES metabolites. These data suggest that an analogous in vivo modification in the transcriptionally active chromatin histones by DES metabolites may influence gene function.

Animals↗