SEARCH · Search PubMed

Results for “Histone Modifications”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,351 records · Page 75Linked to original sources

PubMed2003

Quantitative characterization of specific genomic promoters using agarose gel electrophoresis.

Over the past decade a large number of studies have focused attention on the role of nucleosomes as negative and positive regulators of specific nuclear functions. Due to the lack of an analytical method to determine the higher order conformation of the nucleosomal arrays that encompass specific genetic loci (e.g., promoters, enhancers), research emphasis has mostly been centered on chromatin remodeling and histone posttranslational modifications. We have recently developed an agarose gel electrophoresis method that permits us to analyze the higher order structure of specific in vivo assembled chromatin fragments. After calibration using a well-defined in vitro system, we have been able to experimentally determine the size, shape, and conformational flexibility of the Mouse Mammary Tumor Virus long-terminal repeat promoter region in its repressed and activated states. These studies pave the way for widespread analyses of the higher order structure of specific, functionally important chromosomal loci, and in so doing enhance our understanding of the roles that the higher order structure of chromatin play in genome regulations.

Animals↗

PubMed2007

The nexus of iron and inflammation in hepcidin regulation: SMADs, STATs, and ECSIT.

Hereditary hemochromatosis, characterized by iron overload in multiple organs, is one of the most common genetic disorders among Caucasians. Hepcidin, which is synthesized in the liver, plays important roles in iron overload syndromes. Here, we show that a Cre-loxP-mediated liver-specific disruption of SMAD4 results in markedly decreased hepcidin expression and accumulation of iron in many organs, which is most pronounced in liver, kidney, and pancreas. Transcript levels of genes involved in intestinal iron absorption, including Dcytb, DMT1, and ferroportin, are significantly elevated in the absence of hepcidin. We demonstrate that ectopic overexpression of SMAD4 activates the hepcidin promoter and is associated with epigenetic modification of histone H3 to a transcriptionally active form. Moreover, transcriptional activation of hepcidin is abrogated in SMAD4-deficient hepatocytes in response to iron overload, TGF-beta, BMP, or IL-6. Our study uncovers a novel role of TGF-beta/SMAD4 in regulating hepcidin expression and thus intestinal iron transport and iron homeostasis [corrected]

Comment↗

PubMed2003

Rapid onset of nucleolar disintegration preceding cell cycle arrest in roscovitine-induced apoptosis of human MCF-7 breast cancer cells.

The aim of our study was to explore the antiproliferative and pro-apoptotic action of roscovitine (ROSC) on human breast cancer MCF-7 cells. We examined the effect of ROSC on cell proliferation, cell cycle progression, nucleolar morphology, posttranslational modifications of histones as well as on induction of apoptosis. The effects of ROSC on the argyrophilic nucleolar organizer regions (AgNORs) and nucleolar RNA of MCF-7 cells were marked: ROSC treatment changed the pattern of AgNORs in a time-dependent manner. The disintegration of nucleoli manifested by increasing number of nucleolar fragments already began at 6 hr posttreatment. This was accompanied by a redistribution of the nucleolin from the nucleolus beginning after 6 hr and preceded a decrease of histone acetylation and phosphorylation. Inhibition of DNA synthesis and accumulation of G(2)/M-arrested cells starting 6 hr posttreatment coincided with a strong increase of the p53 level and with an appearance of a few cells committed to undergo apoptosis. However, all these changes preceded the main wave of apoptosis, which occurred after 24 hr ROSC treatment as assessed by determination of the frequency of Annexin binding, activation of caspases as well as of DNA fragmentation. Onset of PARP-1 cleavage detected by immunoblotting and by immunohistochemistry 6 hr or 9 hr posttreatment, respectively, preceded for a few hours the DNA fragmentation detected in situ by TUNEL assay. Reconstitution of MCF-7 cells with caspase-3 did not change the kinetics of ROSC-induced apoptosis. Our results show that disintegration of nucleoli is an early marker of ROSC-induced changes. Cell cycle arrest precedes the main wave of apoptosis.

Acetylation↗

PubMed2003

Epigenetic regulation of Igf2/H19 imprinting at CTCF insulator binding sites.

The mouse insulin-like growth factor II (Igf2) and H19 genes are located adjacent to each other on chromosome 7q11-13 and are reciprocally imprinted. It is believed that the allelic expression of these two genes is regulated by the binding of CTCF insulators to four parent-specific DNA methylation sites in an imprinting control center (ICR) located between these two genes. Although monoallelically expressed in peripheral tissues, Igf2 is biallelically transcribed in the CNS. In this study, we examined the allelic DNA methylation and CTCF binding in the Igf2/H19 imprinting center in CNS, hypothesizing that the aberrant CTCF binding as one of the mechanisms leads to biallelic expression of Igf2 in CNS. Using hybrid F1 mice (M. spretus males x C57BL/6 females), we showed that in CNS, CTCF binding sites in the ICR were methylated exclusively on the paternal allele, and CTCF bound only to the unmethylated maternal allele, showing no differences from the imprinted peripheral tissues. Among three other epigenetic modifications examined, histone H3 lysine 9 methylation correlated well with Igf2 allelic expression in CNS. These results suggest that CTCF binding to the ICR alone is not sufficient to insulate the Igf2 maternal promoter and to regulate the allelic expression of the gene in the CNS, thus challenging the aberrant CTCF binding as a common mechanism for lack of Igf2 imprinting in CNS. Further studies should be focused on the identification of factors that are involved in histone methylation and CTCF-associated factors that may be needed to coordinate Igf2 imprinting.

Acetylation↗

PubMed2003

Epsilon -N,N,N-trimethyllysine-specific ions in matrix-assisted laser desorption/ionization-tandem mass spectrometry.

Epsilon -N,N,N-trimethyllysine (K(me3)) is a component of a number of proteins and plays an important role in the expression of their biological functions. Trimethylation, which causes an incremental increase in mass of 42.0470 Da from that of the corresponding MH(+) ion, cannot be distinguished from the acetylation (+42.0106 Da), which also occurs on epsilon-amino groups of Lys or alpha-amino groups in many proteins, without high-accuracy mass measurement which is accurate to within the second decimal place. MALDI-MS and MS/MS have been applied for the analyses of post-translational modifications of histone H3, which is known to contain both multiple acetylation and methylation sites in its sequence. During the measurements of the modified peptides, a novel fragmentation which involves the loss of trimethylamine from K(me3) was found. This characteristic fragmentation, which was observed to produce ions separated by 59 Da from the conventional precursor ion or sequence ions, would be useful for probing K(me3) units in the sequence.

Acetylation↗

PubMed2005

Epigenetic inheritance of chromatin states mediated by Polycomb and trithorax group proteins in Drosophila.

Proteins of the Polycomb group (PcG) and of the trithorax group (trxG) are involved in the regulation of key developmental genes, such as homeotic genes. PcG proteins maintain silent states of gene expression, while the trxG of genes counteracts silencing with a chromatin opening function. These factors form multimeric complexes that act on their target chromatin by regulating post-translational modifications of histones as well as ATP-dependent remodelling of nucleosome positions. In Drosophila, PcG and trxG complexes are recruited to specific DNA elements named as PcG and trxG response elements (PREs and TREs, respectively). Once recruited, these complexes seem to be able to establish silent or open chromatin states that can be inherited through multiple cell divisions even after decay of the primary silencing or activating signal. In recent years, many components of both groups of factors have been characterized, and the molecular mechanisms underlying their recruitment as well as their mechanism of action on their target genes have been partly elucidated. This chapter summarizes our current knowledge on these aspects and outlines crucial open questions in the field.

Animals↗

PubMed2007

Emerging role for microRNAs in acute promyelocytic leukemia.

Hematopoiesis is highly controlled by lineage-specific transcription factors that, by interacting with specific DNA sequences, directly activate or repress specific gene expression. These transcription factors have been found mutated or altered by chromosomal translocations associated with leukemias, indicating their role in the pathogenesis of these malignancies. The post-genomic era, however, has shown that transcription factors are not the only key regulators of gene expression. Epigenetic mechanisms such as DNA methylation, posttranslational modifications of histones, remodeling of nucleosomes, and expression of small regulatory RNAs all contribute to the regulation of gene expression and determination of cell and tissue specificity. Deregulation ofthese epigenetic mechanisms cooperates with genetic alterations to the establishment and progression of tumors. MicroRNAs (miRNAs) are negative regulators of the expression of genes involved in development, differentiation, proliferation, and apoptosis. Their expression appears to be tissue-specific and highly regulated according to the cell's developmental lineage and stage. Interestingly, miRNAs expressed in hematopoietic cells have been found mutated or altered by chromosomal translocations associated with leukemias. The expression levels of a specific miR-223 correlate with the differentiation fate of myeloid precursors. The activation of both pathways of transcriptional regulation by the myeloid lineage-specific transcription factor C/EBPalpha (CCAAT/enhancer-binding protein-alpha), and posttranscriptional regulation by miR-223 appears essential for granulocytic differentiation and clinical response of acute promyelocytic leukemia (APL) blasts to all-trans retinoic acid (ATRA). Together, this evidence underlies transcription factors, chromatin remodeling, and miRNAs as ultimate determinants for the correct organization of cell type-specific gene arrays and hematopoietic differentiation, therefore providing new targets for the diagnosis and treatment of leukemias.

CCAAT-Enhancer-Binding Protein-alpha↗

PubMed2004

Chromatin modifiers in transcription and DNA repair.

In eukaryotes, the packaging of DNA into nucleosomes and the organization of chromatin fibres generate constraints for all nuclear processes involving DNA, including replication, repair, recombination and transcription. The three major processes that regulate chromatin structure and counterbalance its repressive effects are ATP-dependent chromatin remodeling, post-translational modification of histones and histone replacement. While many of these processes have been intensively studied with respect to their effects on transcription, there is also evidence that they affect other nuclear processes involving DNA. This review explores the functions of chromatin-remodeling factors and histone-modifying enzymes in gene regulation and summarizes recent findings which suggest a role for these chromatin modifiers in DNA repair.

Animals↗

PubMed2004

Biochemistry and biology of mammalian DNA methyltransferases.

DNA methylation is a stable but not irreversible epigenetic signal that silences gene expression. It has a variety of important functions in mammals, including control of gene expression, cellular differentiation and development, preservation of chromosomal integrity, parental imprinting and X-chromosome inactivation. In addition, it has been implicated in brain function and the development of the immune system. Somatic alterations in genomic methylation patterns contribute to the etiology of human cancers and ageing. It is tightly interwoven with the modification of histone tails and other epigenetic signals. Here we review our current understanding of the molecular enzymology of the mammalian DNA methyltransferases Dnmt1, Dnmt3a, Dnmt3b and Dnmt2 and the roles of the enzymes in the above-mentioned biological processes.

Animals↗

PubMed2005

Heterochromatin protein 1: a pervasive controlling influence.

Heterochromatin protein 1 (HP1), a component of condensed chromatin, was discovered more than 10 years ago and subsequently found to play important roles in chromosomal biology and gene silencing. Consistent with the hypothesis that post-translational modifications of histones may functionally 'mark' DNA sequences, HP1 was found to bind to 'silent' chromatin via the methylated lysine 9 (K9) residue on the histone H3 tail that protrudes from the nucleosome. The discovery of several HP1-associating proteins has given us insight into how HP1 may function. Although initially found to localise predominantly at heterochromatin, recent data suggest that HP1 also localises and dynamically participates in gene regulation in euchromatin. Moreover, the initial definition of HP1 as a gene repressor may need to be revisited, as HP1 has been shown, in some cases, to localise at transcriptionally active chromosomal sites. Here we review current knowledge on HP1 and explore possible mechanisms whereby HP1 might exert divergent effects on gene regulation.

Animals↗

PubMed1998

The genetics of epigenetics.

Cis-acting binding sites for transcription activators cannot explain the patterned expression of genes during development, nor a large range of phenomena that result from gene transplacement. Heritable states of transcriptional regression or activation sequences are influenced not only by the chromosomal context of the promoter but also by modifications of histones and DNA, and long-range interactions between distant chromosomal elements. The molecular dissection of these epigenetic phenomena has become an exciting topic of research, revealing highly conserved mechanisms at work in chromatin-mediated gene control.

Animals↗

PubMed2025

Epigenetic maps of pearl millet reveal a prominent role for CHH methylation in regulating tissue-specific gene expression.

UNLABELLED: Pearl millet (Pennisetum glaucum) is a major staple food in arid and semi-arid regions of sub-Saharan Africa, India, and South Asia. However, how epigenetic mechanisms regulate tissue-specific gene expression in this crop remains poorly understood. In this study, we profiled multiple epigenetic features in the young panicles and roots of pearl millet using RNA-seq, ATAC-seq, whole-genome bisulfite sequencing, and ChIP-seq (H3K4me3 and H3K36me3). We identified thousands of genes that were differentially expressed between these two tissues. Root-specific genes were enriched for plant hormone signaling, oxidative phosphorylation, and stress responses. Analysis of chromatin accessibility revealed that root-specific accessible chromatin regions (ACRs) were enriched in binding motifs for stress-responsive transcription factors (e.g., NAC, WRKY), whereas ACRs in young panicles were enriched in motifs for developmental regulators (e.g., AP2/ERF). DNA methylation profiling revealed 25,141 tissue-specific differentially methylated regions, with CHH methylation-rather than CG or CHG methylation-showing the strongest tissue specificity. Promoters of root-specific genes had higher levels of CHH methylation compared to those of young panicle-specific genes, suggesting that the roles of CHH methylation in regulating transcription might be tissue dependent. Notably, promoter-associated H3K4me3 marked panicle-specific genes, whereas root-specific expression was primarily linked to chromatin accessibility, suggesting a transcription factor-mediated regulatory mechanism. Together, our findings highlight the distinct epigenetic frameworks governing tissue-specific gene expression in pearl millet and provide valuable insights for advancing the genetic improvement of this crop. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s42994-025-00243-2.

CHH methylation↗

PubMed2026

Prenatal Androgenization Modifies H3K9me3 Binding in the Promoter of the Androgen Receptor Gene in the Arcuate Nucleus of the Adult Female Mouse.

Animal models have shown that prenatal exposure to excess androgens is associated with the development of polycystic ovary syndrome (PCOS) features. We have identified that prenatally androgenized (PNA) mice modelling PCOS show suppressed androgen receptor mRNA (Ar) expression in the arcuate nucleus (ARC) across development. This could contribute to PCOS-related impaired gonadal steroid hormone feedback to GnRH neurons. However, the mechanism of Ar mRNA suppression following PNA is not determined. We performed a chromatin immunoprecipitation (ChIP) assay coupled with quantitative PCR (qPCR) to investigate histone and transcription factor binding within the Ar gene promoter or enhancer regions in the ARC of female mice at postnatal day (P)60 or gestational day (GD)18.5. In comparison to adult vehicle control (VEH) mice, our ChIP-qPCR revealed that H3K9me3, a repressive histone mark, was increased in adult PNA mice at the promoter regions of the Ar gene. H3K27ac, an active histone mark, and SP1, a transcription factor that acts as a positive regulator of gene expression, were unchanged in the same regions. Increased H3K9me3 seen at the promoter region in adult PNA mice, however, was not observed in the GD18.5 mice ARC following PNA. These results suggest that the deposition of H3K9me3 on the Ar promoter is unlikely to be established by PNA at the time of excess androgen exposure, and instead is likely to be established later in postnatal development or in adulthood. These data provide greater understanding of the developmental mechanisms and timeline underpinning PNA-mediated female dysfunction and PCOS-like reproductive physiology.

Animals↗

PubMed1987

ADPribosylation of nuclear proteins labeled with [3H]adenosine: changes during the HeLa cycle.

Cell cycle variations in the modification of histones and nonhistones by ADPribosylation were investigated. Proteins of HeLa interphase nuclei and metaphase chromosomes were radioactively labeled in vivo with [3H]adenosine. Histones of metaphase chromosomes were extensively modified by ADPribosylation, with H2B, H2A and H4 being predominant acceptors of [3H]adenosine label. For histones of interphase nuclei from synchronized cells, the highest level of 3H labeling was observed by two-dimensional gel electrophoresis to occur in S phase. The minimum level was noted in G1 phase. ADPribosylation of histones is, however, significant during all phases of the cell cycle. These conclusions were confirmed by experiments using [32P]NAD. The results with the specific inhibitor of ADPribosylation, 3-aminobenzamide, and with snake venom phosphodiesterase indicated that the radioactive isotopes were incorporated as ADPribose. Two-dimensional gels of HeLa nonhistones labeled with [3H]adenosine showed strikingly different patterns for interphase and metaphase samples. Over 100 ADPribosylated species were found for interphase nuclei, but poly(ADPribose) polymerase was the only major acceptor for metaphase chromosomes. A simple pattern was also revealed for nuclear scaffolds, with the 'lamins' and poly(ADPribose) polymerase being identifiable as modified species.

Adenosine↗

PubMed2005

A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression.

Alleles↗

PubMed2004

Heterochromatin: RNA points the way.

Mutation of the multi-KH domain protein DPP1, which has single-stranded nucleic acid binding activity, suppresses heterochromatin-mediated silencing in Drosophila; it also disrupts the modification of histone H3 at lysine 9, and association of heterochromatin protein 1 on the heterochromatic regions, suggesting a role for DDP1 in heterochromatin formation.

Chromobox Protein Homolog 5↗

PubMedDate not supplied

PARP-1, PARP-2 and ATM in the DNA damage response: functional synergy in mouse development.

Poly(ADP-ribosyl)ation is an immediate DNA damage-dependent posttranslational modification of histones and nuclear proteins that contributes to the survival of injured proliferating cells. Poly(ADP-ribose) polymerases (PARPs) now constitute a superfamily of 18 proteins, encoded by different genes and displaying a common conserved catalytic domain. PARP-1 (113kDa), the founding member, and PARP-2 (62kDa) are both involved in DNA-break sensing and signaling when single strand break repair (SSBR) or base excision repair (BER) pathways are engaged. The generation by homologous recombination of deficient mouse models have confirmed the caretaker function of PARP-1 and PARP-2 in mammalian cells under genotoxic stress. This review summarizes our present knowledge on their physiological role in the cellular response to DNA damage and on the genetic interactions between PARP-1, PARP-2, Atm that play an essential role during early embryogenesis.

Animals↗

PubMed2005

Transcriptional regulation and the role of diverse coactivators in animal cells.

Transcriptional regulation in eukaryotes involves structurally and functionally distinct nuclear RNA polymerases, corresponding general initiation factors, gene-specific (DNA-binding) regulatory factors, and a variety of coregulatory factors that act either through chromatin modifications (e.g. histone acetyltransferases and methyltransferases) or more directly (e.g. Mediator) to facilitate formation and function of the preinitiation complex. Biochemical studies with purified factors and DNA versus recombinant chromatin templates have provided insights into the nature and mechanism of action of these factors, including pathways for their sequential function in chromatin remodeling and preinitiation complex formation/function (transcription) steps and a possible role in facilitating the transition between these steps.

Animals↗