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PubMed2006

The development of archosaurian first-generation teeth in a chicken mutant.

Modern birds do not have teeth. Rather, they develop a specialized keratinized structure, called the rhamphotheca, that covers the mandible, maxillae, and premaxillae. Although recombination studies have shown that the avian epidermis can respond to tooth-inductive cues from mouse or lizard oral mesenchyme and participate in tooth formation, attempts to initiate tooth development de novo in birds have failed. Here, we describe the formation of teeth in the talpid2 chicken mutant, including the developmental processes and early molecular changes associated with the formation of teeth. Additionally, we show recapitulation of the early events seen in talpid2 after in vivo activation of beta-catenin in wild-type embryos. We compare the formation of teeth in the talpid2 mutant with that in the alligator and show the formation of decidedly archosaurian (crocodilian) first-generation teeth in an avian embryo. The formation of teeth in the mutant is coupled with alterations in the specification of the oral/aboral boundary of the jaw. We propose an epigenetic model of the developmental modification of dentition in avian evolution; in this model, changes in the relative position of a lateral signaling center over competent odontogenic mesenchyme led to loss of teeth in avians while maintaining tooth developmental potential.

Alligators and Crocodiles↗

PubMed2005

Effects of Histone Deacetylase Inhibitor (HDACi); Trichostatin-A (TSA) on the expression of housekeeping genes.

In quantitative RT-PCR (qRT-PCR), analysis of gene expression is dependent on normalization using housekeeping genes such as 18S rRNA, GAPDH and beta actin. However, variability in their expression has been reported to be caused by factors like drug treatment, pathological states and cell-cycle phase. An emerging area of cancer research focuses on identifying the role of epigenetic alterations such as histone modifications and DNA methylation in the initiation and progression of cancer. Histone acetylation is the best studied modification so far and has been probed through the use of histone deacetylase inhibitors (HDACi). Further, modulation of histone acetylation is currently being explored as a therapeutic strategy in the treatment of cancer and HDACis have shown promise in inhibiting tumorigenesis and metastasis. Trichostatin-A (TSA) is the most widely used HDACi. Therefore, we were driven to identify a suitable internal control for RT-PCR following TSA treatment. We performed quantitative RT-PCR analysis using mouse prostate tissue explants, human prostate cancer (LNCaP) cells and human breast cancer (T-47D and ZR-75-1) cells following TSA treatment. Expression of housekeeping genes including 18S rRNA, beta actin, GAPDH and ribosomal highly-basic 23-kDa protein (rb 23-kDa, RPL13A) were compared in vehicle versus TSA treated samples. Our results showed marked variations in 18S rRNA, beta actin mRNA and GAPDH mRNA levels in mouse prostate explants and a human prostate cancer (LNCaP) cell line following TSA treatment. Furthermore, in two human breast cancer cell lines (T-47D and ZR-75-1) 18S rRNA, beta actin mRNA and GAPDH mRNA levels varied significantly. However, RPL13A mRNA levels remained constant in all the conditions tested. Therefore, we recommend use of RPL13A as a standard for normalization during TSA treatment.

Actins↗

PubMed2005

Epigenetic silencing in embryogenesis.

Transcription profiling of early embryos emphasizes that differential gene expression is a fundamental control mechanism of development. Precise regulatory mechanisms operate on a background of epigenetic changes in chromatin composition, modification, and architecture that are integral for the development of a pluripotent embryo into an adult.

Animals↗

PubMed2002

Identification of putative interaction partners for the Xenopus Polycomb-group protein Xeed.

The extra sex combs (esc) gene of Drosophila and its mammalian homologue embryonic ectoderm development (eed) play pivotal roles in establishing Polycomb-group (Pc-G) mediated transcriptional silencing of regulatory genes during early development. We have carried out a two-hybrid screen in yeast to identify maternally expressed proteins that interact directly with the product of the Xenopus eed homologue, Xeed. Xeed-interacting proteins that were recovered in this screen included a maternal Xenopus histone deacetylase (HDACm), the Xeed protein itself, and a Xenopus homologue of Enhancer of zeste (XEZ) - a second member of the Pc-G that is closely related by sequence similarity to histone methyltransferases. We have also identified a novel interaction between Xeed and a component of the Xenopus basal transcription machinery, TAF(II)32. We show for the first time that each of these proteins interacts with the Xeed polypeptide, both in the yeast two-hybrid assay and in vitro using purified recombinant proteins. XEZ, HDACm and TAF(II)32 mRNAs are all strongly co-expressed with Xeed mRNA in the fertilized egg, further suggesting that their encoded proteins could interact with Xeed during early embryonic development. Our observations support a multi-step model for the onset of transcriptional silencing in which Xeed binds to and inhibits the function of the transcription initiation complex and also recruits proteins that mediate the acquisition by associated chromatin of epigenetically heritable, post-translational modifications.

Amino Acid Sequence↗

PubMed2001

Re-SET-ting heterochromatin by histone methyltransferases.

Histone methylation was first described more than 35 years ago, but its role has remained enigmatic. Proposed functions range from transcriptional regulation to the higher-order packaging of chromatin in preparation for mitotic condensation. Histone methylation can occur on Arg or Lys residues, with an exquisite site selectivity for Lys methylation at specific positions in the N-termini of histones H3 and H4. Thus, Lys methylation joins acetylation and phosphorylation as a third component of a 'histone code' that modifies the underlying chromatin structure of the genetic information. Notably, in contrast to acetylation and phosphorylation, Lys methylation appears to be a relatively stable histone modification, thereby providing an ideal epigenetic mark for more long-term maintenance of chromatin states. The recent discovery of the first histone Lys methyltransferase has allowed the identification of a molecular mechanism in which the specific methylation of histone H3 at Lys9 generates a binding site for heterochromatin-associated proteins. These findings have broad implications for the overall functional organization of chromosome structure at constitutive heterochromatin (e.g. centromeres) and for chromatin-dependent inheritance of gene expression patterns. This review discusses how understanding this methylation system should address some of the long-standing mysteries of heterochromatin.

Amino Acid Sequence↗

PubMed2007

Heterochromatin revisited.

The formation of heterochromatin, which requires methylation of histone H3 at lysine 9 and the subsequent recruitment of chromodomain proteins such as heterochromatin protein HP1, serves as a model for the role of histone modifications and chromatin assembly in epigenetic control of the genome. Recent studies in Schizosaccharomyces pombe indicate that heterochromatin serves as a dynamic platform to recruit and spread a myriad of regulatory proteins across extended domains to control various chromosomal processes, including transcription, chromosome segregation and long-range chromatin interactions.

Animals↗

PubMed2007

Selective recognition of acetylated histones by bromodomains in transcriptional co-activators.

Bromodomains are present in many chromatin-associated proteins such as the SWI/SNF and RSC chromatin remodelling and the SAGA HAT (histone acetyltransferase) complexes, and can bind to acetylated lysine residues in the N-terminal tails of the histones. Lysine acetylation is a histone modification that forms a stable epigenetic mark on chromatin for bromodomain-containing proteins to dock and in turn regulate gene expression. In order to better understand how bromodomains read the 'histone code' and interact with acetylated histones, we have tested the interactions of several bromodomains within transcriptional co-activators with differentially acetylated histone tail peptides and HAT-acetylated histones. Using GST (glutathione S-transferase) pull-down assays, we show specificity of binding of some bromodomains to differentially acetylated H3 and H4 peptides as well as HAT-acetylated histones. Our results reveal that the Swi2/Snf2 bromodomain interacts with various acetylated H3 and H4 peptides, whereas the Gcn5 bromodomain interacts only with acetylated H3 peptides and tetra-acetylated H4 peptides. Additionally we show that the Spt7 bromodomain interacts with acetylated H3 peptides weakly, but not with acetylated H4 peptides. Some bromodomains such as the Bdf1-2 do not interact with most of the acetylated peptides tested. Results of the peptide experiments are confirmed with tests of interactions between these bromodomains and HAT-acetylated histones. Furthermore, we demonstrate that the Swi2/Snf2 bromodomain is important for the binding and the remodelling activity of the SWI/SNF complex on hyperacetylated nucleosomes. The selective recognition of the bromodomains observed in the present study accounts for the broad effects of bromodomain-containing proteins observed on binding to histones.

Acetylation↗

PubMed2025

Post-translational modifications of the nucleoid protein H-NS: sites, mechanisms, and regulatory cues.

Histone-like nucleoid structuring protein H-NS plays a pivotal role in orchestrating bacterial chromatin and regulating horizontal gene transfer (HGT) elements. In response to environmental signals, H-NS undergoes dynamic post-translational modifications (PTMs) that resemble the epigenetic codes of eukaryotic histones. This review explores how environmental cues regulate PTMs at specific sites within distinct domains of H-NS, thereby modulating its oligomerization and DNA-binding capabilities to reprogram bacterial responses. Notably, HGT elements commonly encode counter-silencing factors, including PTM-modifying enzymes, that counteract H-NS repression. We propose that combinatorial PTM patterns on H-NS form the bacterial histone-like epigenetic code, regulating the expression of HGT elements. Collectively, these interactions establish a sophisticated network of silencing and counter-silencing mechanisms that drive bacterial genome evolution.

Protein Processing, Post-Translational↗

PubMed2005

Nutrition and aberrant DNA methylation patterns in atherosclerosis: more than just hyperhomocysteinemia?

Methylation is a reversible modification of DNA participating in epigenetic regulation of gene expression. It is now clear that atherosclerosis is associated with aberrant DNA methylation patterns in the vascular tissue and peripheral blood cells, but the origin of this anomaly is poorly understood. Based on evidence that global DNA hypomethylation coexists with hyperhomocysteinemia in advanced human atherosclerosis, it is widely assumed that altered DNA methylation patterns in atherosclerosis are mainly secondary to a decrease in factors essential for the synthesis of S-adenosyl methionine (SAM, the main methyl group donor in DNA methylation reactions), such as folate and vitamin B-12, or to homocysteine-induced blocking of SAM biosynthesis. Nonetheless, recent work expanded this view by showing that both local DNA hyper- and hypomethylation occur in early atherosclerosis in normohomocysteinemic mice and that atherogenic lipoprotein profiles promote DNA hypermethylation in cultured human macrophages. These findings suggest that during early atherosclerosis, nutritional factors affect DNA methylation patterns by mechanisms that are likely to be independent of vitamin or homocysteine levels. These data have the potential to assist in the identification of preventive or therapeutic avenues for cardiovascular disease.

Arteriosclerosis↗

PubMed2006

Regulation of imprinted DNA methylation.

DNA methylation is an essential enzymatic modification in mammals. This common epigenetic mark occurs predominantly at the fifth carbon of cytosines within the palindromic dinucleotide 5'-CpG-3'. The majority of methylated CpGs are located within repetitive elements including centromeric repeats, satellite sequences and gene repeats encoding ribosomal RNAs. CpG islands, frequently located at the 5' end of genes, are typically unmethylated. DNA methylation also occurs at imprinted genes which exhibit parent-of-origin-specific patterns of methylation and expression. Imprinted methylation at differentially methylated domains (DMDs) is one of the regulatory mechanisms controlling the allele-specific expression of imprinted genes. Proper control of DNA methylation is needed for normal development and loss of methylation control can contribute to initiation and progression of tumorigenesis (reviewed in Plass and Soloway, 2002). Because patterns of imprinted DNA methylation are highly reproducible, imprinted loci make useful models for studying regulation of DNA methylation and may provide insights into how this regulation goes awry in cancer. Here, we review what is currently known about the mechanisms regulating imprinted DNA methylation. We will focus on cis-acting DNA sequences, trans-acting protein factors and the possible involvement of RNAs in control of imprinted DNA methylation.

Animals↗

PubMed2006

Cloning and characterization of mr-s, a novel SAM domain protein, predominantly expressed in retinal photoreceptor cells.

BACKGROUND: Sterile alpha motif (SAM) domains are approximately 70 residues long and have been reported as common protein-protein interaction modules. This domain is found in a large number of proteins, including Polycomb group (PcG) proteins and ETS family transcription factors. In this work, we report the cloning and functional characterization of a novel SAM domain-containing protein, which is predominantly expressed in retinal photoreceptors and the pineal gland and is designated mouse mr-s (major retinal SAM domain protein). RESULTS: mr-s is evolutionarily conserved from zebrafish through human, organisms through which the mechanism of photoreceptor development is also highly conserved. Phylogenetic analysis suggests that the SAM domain of mr-s is most closely related to a mouse polyhomeotic (ph) ortholog, Mph1/Rae28, which is known as an epigenetic molecule involved in chromatin modifications. These findings provide the possibility that mr-s may play a critical role by regulating gene expression in photoreceptor development. mr-s is preferentially expressed in the photoreceptors at postnatal day 3-6 (P3-6), when photoreceptors undergo terminal differentiation, and in the adult pineal gland. Transcription of mr-s is directly regulated by the cone-rod homeodomain protein Crx. Immunoprecipitation assay showed that the mr-s protein self-associates mainly through the SAM domain-containing region as well as ph. The mr-s protein localizes mainly in the nucleus, when mr-s is overexpressed in HEK293T cells. Moreover, in the luciferase assays, we found that mr-s protein fused to GAL4 DNA-binding domain functions as a transcriptional repressor. We revealed that the repression activity of mr-s is not due to a homophilic interaction through its SAM domain but to the C-terminal region. CONCLUSION: We identified a novel gene, mr-s, which is predominantly expressed in retinal photoreceptors and pineal gland. Based on its expression pattern and biochemical analysis, we predict that mr-s may function as a transcriptional repressor in photoreceptor cells and in pinealocytes of the pineal gland.

Animals↗

PubMedDate not supplied

[Plant life evoluton: opinions and suppositions].

Evolution of plant life has been considered in the context of phylembryogenesis or heterochronia. Hewever, suggested opinions and suppositions regarding the mechanisms, direction and rate of evolutionary changes are opposite. Concepts of phylembryogenesis and heterochronia originally were developed for the different levels of organization and could be distinguished by different modes of morphological evolution. In this connection, interpretations of evolutional changes of shoots morphogenesis, ontogenesis and plant habitus by different types of heterochronia and modes of phylembryogenesis were delineated. It was proposed that evolution of plants life forms could be considered regarding functional specialization of root-shoot (the basic element of life form structure) that appears as metamorphoses of bud, root and shoot. Evolutional changes of root-shoot could take places at the different stages of development due to anabolies (modifications). At the same time epigenetic and episelectional (organic selection) mechanisms of evolution play an important role in the evolution of plant life forms. Moreover, results of modern genetic and molecular phylogenetic investigations produce evidences for the saltations and reversions in the plant life forms evolution.

Biological Evolution↗

PubMed1997

Monozygotic twins discordant for the oculo-oto-radial syndrome (IVIC syndrome).

Monozygotic twins are rarely completely identical despite their origin from a single zygote. The twinning process itself, or the very early intrauterine environment must provide the clues to explain this developmental dilemma. We present here discordant monozygotic twin girls, one of whom was diagnosed having IVIC (Oculo-oto-radial) syndrome on the basis of hand abnormalities and hearing loss but her twin sister has only strabismus. The family has at least 7 apparently and 2 possible affected members (gene carriers) over four generations, the majority being only midly affected. The 2 girls, whose monozygosity has been proved using independent DNA loci, show marked variability in expression, showing that for this gene modification of expression must be epigenetic or environmental rather than genetic.

Child, Preschool↗

PubMed2003

Components of a pathway maintaining histone modification and heterochromatin protein 1 binding at the pericentric heterochromatin in Mammalian cells.

Heterochromatin is a higher order chromatin structure that is important for transcriptional silencing, chromosome segregation, and genome stability. The establishment and maintenance of heterochromatin is regulated not only by genetic elements but also by epigenetic elements that include histone tail modification (e.g. acetylation and methylation) and DNA methylation. Here we show that the p33ING1-Sin3-HDAC complex as well as DNA methyltransferase 1 (DNMT1) and DNMT1-associated protein 1 (DMAP1) are components of a pathway required for maintaining proper histone modification and heterochromatin protein 1 binding at the pericentric heterochromatin. p33ING1 and DMAP1 interact physically and co-localize to heterochromatin in the late S phase, and both are required for heterochromatin protein 1 binding to heterochromatin. Although the p33ING1-Sin3-HDAC and DMAP1-DNMT1 complexes are recruited independently to pericentric heterochromatin regions, they are both required for deacetylation of histones and methylation of histone H3 at lysine 9. These data support a cooperative model for histone deacetylation, methylation, and DNA methylation in maintaining pericentric heterochromatin structure throughout cell divisions.

Chromobox Protein Homolog 5↗

PubMed2026

Epigenetics and In Silico Transcriptome Analysis of Pediatric Acute Myeloid Leukemia.

Pediatric acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that accounts for about 15%-20% of childhood leukemias. Despite therapeutic advances, relapses remain common, and survival for high-risk patients is below 60%. Unlike adult AML, pediatric AML displays distinct genetic mutations, including FLT3-ITD, NPM1, KMT2A rearrangements, and core-binding factors (CBF) fusions, as well as extensive epigenetic dysregulation. Aberrant DNA methylation, histone modifications, and altered non-coding RNA expressions disrupt hematopoietic differentiation and activate oncogenic transcriptional networks. Recent advances in silico transcriptomic analysis have transformed the study of pediatric AML by integrating gene expression and epigenetic data to identify molecular drivers and regulatory networks. Computational RNA-seq pipelines and pathway analyses have highlighted key epigenetic regulators, including DNMT3A, TET2, and HDACs, as potential therapeutic targets. Multi-omics approaches combining transcriptomic, methylomic, and chromatin accessibility data are increasingly used to define biomarkers for diagnosis, prognosis, and therapeutic response. This review provides a comprehensive overview of the molecular and epigenetic landscape of pediatric AML, emphasizing the power of in silico transcriptome analysis to uncover disease mechanisms, refine patient stratification, and guide the development of precision-based epigenetic therapies aimed at improving long-term outcomes in children with AML.

Humans↗

PubMed2001

Involvement of histone H4 acetylation in the epigenetic inheritance of different activity states of maternally and paternally derived genomes in the mealybug Planococcus citri.

Modification of histones by acetylation is a well-known mechanism for the establishment and maintenance of specific chromatin structures with different activity states. In Planococcus citri males the paternal genome, early in development, becomes mostly inactive and heterochromatic. As we had not found methylation in the genome of P. citri, we analyzed the acetylation state of histone H4. We report here that, in males, differences in the level of histone H4 acetylation are indeed present in the two genomes of different parental origin; these differences were confirmed by treatment with the histone deacetylase inhibitor Trichostatin A. There is also evidence of acetylation of histone H4 on metaphase chromosomes. Our data therefore suggest a role of histone H4 acetylation in the imprinting of the paternal genome in P. citri males, thus supporting a role of modification of chromatin-related structural proteins in the epigenetic transmission of imprinting.

Acetylation↗

PubMed2025

Analog epigenetic memory revealed by targeted chromatin editing.

Cells store information by means of chromatin modifications that persist through cell divisions and can hold gene expression silenced over generations. However, how these modifications may maintain other gene expression states has remained unclear. This study shows that chromatin modifications can maintain a wide range of gene expression levels over time, thus uncovering analog epigenetic memory. By engineering a genomic reporter and epigenetic effectors, we tracked the gene expression dynamics following targeted perturbations to the chromatin state. We found that distinct grades of DNA methylation led to corresponding, persistent gene expression levels. Altering the DNA methylation grade, in turn, resulted in permanent loss of gene expression memory. Consistent with experiments, our chromatin modification model indicates that analog memory arises when the positive feedback between DNA methylation and repressive histone modifications is lacking. This discovery will lead to a deeper understanding of epigenetic memory and to new tools for synthetic biology.

Epigenesis, Genetic↗

PubMed2006

Histone-modifying enzymes: encrypting an enigmatic epigenetic code.

Histone-modifying enzymes catalyze a diverse array of post-translational modifications of core and linker histones within chromatin. These modifications govern a multitude of genomic functions, particularly gene expression, and are believed to constitute an epigenetic code. Histone-modifying enzymes inscribe this code by catalyzing site-selective modifications, which are subsequently interpreted by effector proteins that recognize specific covalent marks. The substrate specificity of these enzymes is of fundamental biological importance because it underpins this epigenetic code. Recently, the structural basis of this specificity has been examined with regards to recently determined structures of GCN5 acetyltransferases and SET domain methyltransferases in complex with their cognate histone substrates.

Animals↗