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Chromosomal inactivation of Bacillus subtilis exfusants: a prokaryotic model of epigenetic regulation.

Epigenetic mechanisms are not exclusively reserved to eukaryotic organisms. They are also observed in prokaryotes. As described first by Hotchkiss and Gabor, protoplast fusion between strains of Bacillus subtilis produces heterodiploid cells. Heterodiploidy is associated with the inactivation of one of the chromosomes. To study the physical structure of the fusion product and the molecular mechanisms of inactivation, we constructed heterodiploid clones containing two chromosomes labeled by a NotI restriction fragment length polymorphism. In the progeny, we identified haploid recombinant clones that contain a chromosome carrying large regions of inactivated DNA. Studies of both recombinants of the latter kind and heterodiploid cells indicated that chromosomal inactivation was not determined by alteration of the inactivated nucleotide sequence, but was probably due to a modification in the structure of the bacterial chromatin.

Bacillus subtilis↗

PubMed2006

Epigenetic regulation of integrin-linked kinase expression depending on adhesion of gastric carcinoma cells.

Cell adhesion to the extracellular matrix (ECM) regulates gene expressions in diverse dynamic environments. However, the manner in which gene expressions are regulated by extracellular cues is largely unknown. In this study, suspended gastric carcinoma cells showed higher basal and transforming growth factor-beta1 (TGFbeta1)-mediated acetylations of histone 3 (H3) and Lys(9) of H3 and levels of integrin-linked kinase (ILK) mRNA and protein than did fibronectin-adherent cells did. Moreover, the insignificant acetylation and ILK expression in adherent cells were recovered by alterations of integrin signaling and actin organization, indicating a connection between cytoplasmic and nuclear changes. Higher acetylations in suspended cells were correlated with associations between Smad4, p300/CBP, and Lys(9)-acetylated H3. Meanwhile, adherent cells showed more associations between HDAC3, Ski, and MeCP2. Chromatin immunoprecipitations with anti-acetylated H3, Lys(9)-acetylated H3, or p300/CBP antibody resulted in more coprecipitated ILK promoter, correlated with enhanced ILK mRNA and protein levels, in suspended cells. Moreover, ILK expression inversely regulated cell adhesion to ECM proteins, and its overexpression enhanced cell growth in soft agar. These observations indicate that cell adhesion and/or its related molecular basis regulate epigenetic mechanisms leading to a loss of ILK transcription, which in turn regulates cell adhesion property in a feedback linkage.

Acetylation↗

PubMed2006

Epigenetic regulation of varicella-zoster virus open reading frames 62 and 63 in latently infected human trigeminal ganglia.

Open reading frames (ORFs) 21, 29, 62, 63, and 66 of varicella-zoster virus (VZV) are transcribed during latency in human ganglia. ORF 63 is the most frequently expressed gene, and ORF 62 encodes a transcriptional activator. The mechanisms regulating the expression of these genes are not well understood, although analyses of other alphaherpesviruses indicate a role for chromatin in virus gene regulation during latent infection. Using chromatin immunoprecipitation (ChIP) assays to analyze the euchromatic state of ORFs 62 and 63 compared to the centromere from human chromosome 4 (heterochromatic) and the human glyceraldehyde-3-phosphate dehydrogenase promoter (euchromatic), we show that the promoters of ORFs 62 and 63 are associated with the histone protein H3K9(Ac) and thus maintained in a euchromatic state during latency. Conversely, the promoters of ORF 36 (thymidine kinase) and ORF 14 (glycoprotein C), genes expressed during lytic but not latent infection, were not enriched in the fraction of latently infected ganglia that bound to anti-H3K9(Ac) antibody. A ChIP assay using productively infected MeWo cells revealed that VZV ORFs 62, 63, 36, and 14 are all euchromatic. Together, these data indicate that the expression of the two latency-related VZV genes, ORFs 62 and 63, is regulated epigenetically through chromatin structure.

Acetylation↗

PubMed2002

Single-molecule analysis reveals clustering and epigenetic regulation of replication origins at the yeast rDNA locus.

How eukaryotes specify their replication origins is an important unanswered question. Here, we analyze the replicative organization of yeast rDNA, which consists of approximately 150 identical repeats, each containing a potential origin. Using DNA combing and single-molecule imaging, we show that functional rDNA origins are clustered and interspersed with large domains where initiation is silenced. This repression is largely mediated by the Sir2p histone-deacetylase. Increased origin firing in sir2 Delta mutants leads to the accumulation of circular rDNA species, a major determinant of yeast aging. We conclude that rDNA replication is regulated epigenetically and that Sir2p may promote genome stability and longevity by suppressing replication-dependent rDNA recombination.

DNA Replication↗

PubMed2006

Epigenetic regulation in Drosophila.

Epigenetic regulation of gene transcription relies on molecular marks like DNA methylation or histone modifications. Here we review recent advances in our understanding of epigenetic regulation in the fruit fly Drosophila melanogaster. In the past, DNA methylation research has primarily utilized mammalian model systems. However, several recent landmark discoveries have been made in other organisms. For example, the interaction between DNA methylation and histone methylation was first described in the filamentous fungus Neurospora crassa. Another example is provided by the interaction between epigenetic modifications and the RNA interference (RNAi) machinery that was first reported in the fission yeast Schizosaccharomyces pombe. Another organism with great experimental power is the fruit fly Drosophila. Epigenetic regulation by chromatin has been extensively analyzed in the fly and several of the key components have been discovered in this organism. In this chapter, we will focus on three aspects that represent the complexity of epigenetic gene regulation. (1) We will discuss the available data about the DNA methylation system, (2) we will illuminate the interaction between DNA methylation and chromatin regulation, and (3) we will provide an overview over the Polycomb system of epigenetic chromatin modifiers that has proved to be an important paradigm for a chromatin system regulating epigenetic programming.

Acetylation↗

PubMed2004

Onset and inheritance of abnormal epigenetic regulation in hematopoietic cells.

Abnormal epigenetic regulation of gene expression contributes significantly to a variety of human pathologies including cancer. Deletion of hypersensitive site 2 (HS2) at the human beta-globin locus control region can lead to abnormal epigenetic regulation of globin genes in transgenic mice. Here, two HS2-deleted transgenic mouse lines were used as model to demonstrate that heritable alteration of chromatin organization at the human beta-globin locus in multipotent hematopoietic progenitors contributes to the abnormal expression of the beta-globin gene in mature erythroid cells. This alteration is characterized by specific patterns of histone covalent modifications that are inherited during erythropoiesis and, moreover, is plastic because it can be reverted by transient treatment with the histone deacetylase inhibitor Trichostatin A. Altogether, our results indicate that aberrant epigenetic regulation can be detected and modified before tissue-specific gene transcription, a finding which may lead to novel strategies for the prevention of chromatin-related pathologies.

Acetylation↗

PubMed2003

Polycomb group genes as epigenetic regulators of normal and leukemic hemopoiesis.

Epigenetic modification of chromatin structure underlies the differentiation of pluripotent hemopoietic stem cells (HSCs) into their committed/differentiated progeny. Compelling evidence indicates that Polycomb group (PcG) genes play a key role in normal and leukemic hemopoiesis through epigenetic regulation of HSC self-renewal/proliferation and commitment. The PcG proteins are constituents of evolutionary highly conserved molecular pathways regulating cell fate in several other tissues through diverse mechanisms, including 1) regulation of self-renewal/proliferation, 2) regulation of senescence/immortalization, 3) interaction with the initiation transcription machinery, 4) interaction with chromatin-condensation proteins, 5) modification of histones, 6) inactivation of paternal X chromosome, and 7) regulation of cell death. It is therefore not surprising that PcG genes lead to pleiotropic phenotypes when mutated and have been associated with malignancies in several systems in both mice and humans. Although much remains to be learned regarding the PcG mechanism(s) of action, advances in identifying the functional domains and enzymatic activities of these multimeric protein complexes have provided insights into how PcG proteins accomplish such processes. Some of the new insights into a role for the PcG cellular memory system in regulating normal and leukemic hemopoiesis are reviewed here, with special emphasis on their potential involvement in epigenetic regulation of gene expression through modification of chromatin structure.

Animals↗

PubMed2001

Histone methylation versus histone acetylation: new insights into epigenetic regulation.

Post-translational addition of methyl groups to the amino-terminal tails of histone proteins was discovered more than three decades ago. Only now, however, is the biological significance of lysine and arginine methylation of histone tails being elucidated. Recent findings indicate that methylation of certain core histones is catalyzed by a family of conserved proteins known as the histone methyltransferases (HMTs). New evidence suggests that site-specific methylation, catalyzed by HMTs, is associated with various biological processes ranging from transcriptional regulation to epigenetic silencing via heterochromatin assembly. Taken together, these new findings suggest that histone methylation may provide a stable genomic imprint that may serve to regulate gene expression as well as other epigenetic phenomena.

Acetylation↗

PubMed2000

Epigenetic regulation of androgen receptor gene expression in human prostate cancers.

Epigenetic mechanisms including DNA methylation and histone deacetylation are thought to play important roles in gene transcriptional inactivation. Heterogenous expression of androgen receptor (AR), which appears to be related to variable responses to endocrine therapy in prostate cancer (PCa) may also be due to epigenetic factors. The methylation status of the 5' CpG island of the AR in 3 prostate cancer cell lines and 10 primary and 14 hormone-refractory PCa samples was determined using the bisulfite PCR methods. In DU145, CpG-rich regions of the AR were hypermethylated. By an immunohistochemical analysis, only one PCa sample had no AR expression, the others being heterogenous. Bisulfite sequencing and methylation-specific PCR analysis showed aberrant methylation of AR 5'-regulatory region in 20% of 10 primary and 28% of 14 hormone-refractory PCa samples. To clarify the effect of epigenetic regulation on AR expression, we treated three prostate cancer cell lines with a demethylating agent, 5-aza-2'-deoxycytidine (azaC), and a histone deacetylase inhibitor, Trichostatin A (TSA). In DU145, re-expression of AR mRNA was detected after treatment with azaC and/or TSA. Our results suggest that epigenetic regulations including CpG methylation and histone acetylation may play important roles in the regulation of the AR.

Antimetabolites, Antineoplastic↗

PubMed2006

Epigenetic regulation of human gamma-glutamyl hydrolase activity in acute lymphoblastic leukemia cells.

Gamma-glutamyl hydrolase (GGH) catalyzes degradation of the active polyglutamates of natural folates and the antifolate methotrexate (MTX). We found that GGH activity is directly related to GGH messenger RNA expression in acute lymphoblastic leukemia (ALL) cells of patients with a wild-type germline GGH genotype. We identified two CpG islands (CpG1 and CpG2) in the region extending from the GGH promoter through the first exon and into intron 1 and showed that methylation of both CpG islands in the GGH promoter (seen in leukemia cells from approximately 15% of patients with nonhyperdiploid B-lineage ALL) is associated with significantly reduced GGH mRNA expression and catalytic activity and with significantly higher accumulation of MTX polyglutamates (MTXPG(4-7)) in ALL cells. Furthermore, methylation of CpG1 was leukemia-cell specific and had a pronounced effect on GGH expression, whereas methylation of CpG2 was common in leukemia cells and normal leukocytes but did not significantly alter GGH expression. These findings indicate that GGH activity in human leukemia cells is regulated by epigenetic changes, in addition to previously recognized genetic polymorphisms and karyotypic abnormalities, which collectively determine interindividual differences in GGH activity and influence MTXPG accumulation in leukemia cells.

Adolescent↗

PubMed1999

Epigenetics: regulation through repression.

Epigenetics is the study of heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic phenomena have major economic and medical relevance, and several, such as imprinting and paramutation, violate Mendelian principles. Recent discoveries link the recognition of nucleic acid sequence homology to the targeting of DNA methylation, chromosome remodeling, and RNA turnover. Although epigenetic mechanisms help to protect cells from parasitic elements, this defense can complicate the genetic manipulation of plants and animals. Essential for normal development, epigenetic controls become misdirected in cancer cells and other human disease syndromes.

Animals↗

PubMed2026

Epigenetic Regulation of the BDNF Gene by Molybdenum in 9 to 11-Year-Old Children: A Targeted Gene DNA Methylation Study.

While essential trace minerals are known to influence DNA methylation (DNAm), molybdenum's (Mo) role in epigenetic regulation remains largely unexplored. This study examined associations between Mo status and DNAm of the brain-derived neurotrophic factor (BDNF) gene, a critical regulator of neurogenesis, in children aged 9-11 years, focusing on 107 CpG sites across BDNF and its antisense transcript (BDNF-AS).BDNF and BDNF-AS methylation was analyzed in blood samples from 72 children randomly selected from a cohort of 292 participants. Dietary Mo intake was estimated from food records, and creatinine-adjusted urinary Mo levels were quantified. Higher urinary molybdenum was significantly associated with decreased methylation at five BDNF 5'UTR sites (p<.05) and increased methylation of BDNF-AS (p =  .0001), consistent with enhanced BDNF transcriptional activity. African American children exhibited lower urinary Mo excretion than European American children, suggesting greater retention, and showed cortisol-associated increases in BDNF methylation not observed in European American children.These findings demonstrate associations between molybdenum status and DNA methylation patterns at the BDNF locus in children. While functional validation through BDNF protein measurement is needed, results suggest molybdenum may influence neurotrophin gene regulation through epigenetic mechanisms, highlighting the importance of trace mineral nutrition during neurodevelopment.

Humans↗

PubMed2005

Epigenetic regulation by histone methylation and histone variants.

Epigenetics is the study of heritable changes in gene expression that are not mediated at the DNA sequence level. Molecular mechanisms that mediate epigenetic regulation include DNA methylation and chromatin/histone modifications. With the identification of key histone-modifying enzymes, the biological functions of many histone posttranslational modifications are now beginning to be elucidated. Histone methylation, in particular, plays critical roles in many epigenetic phenomena. In this review, we provide an overview of recent findings that shape the current paradigms regarding the roles of histone methylation and histone variants in heterochromatin assembly and the maintenance of the boundaries between heterochromatin and euchromatin. We also highlight some of the enzymes that mediate histone methylation and discuss the stability and inheritance of this modification.

Amino Acid Sequence↗

PubMed1995

Epigenetic regulation of gene expression: the effect of altered chromatin structure from yeast to mammals.

Epigenetic gene regulation refers to different states of phenotypic expression caused by differential effects of chromosome or chromatin packaging rather than by differences in DNA sequence. Examples of epigenetic regulation can be found in organisms as diverse as the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the fruit fly Drosophila melanogaster, the nematode Caenorhabditis elegans, and mammals. Three major types of epigenetic regulation are considered in this review: dosage compensation, imprinting and position effect variegation. While the specific details and mechanisms of each is quite different, they all involve either local or extensive alterations in chromatin structure. A number of genes implicated in epigenetic regulation have been isolated and their products identified as proteins or RNA molecules involved at various levels in DNA, chromatin or chromosome binding. While in general our understanding of mammalian epigenetic phenomena is not as advanced as that in model systems, the detailed molecular and genetic understanding of processes responsible for conditional gene silencing in invertebrate systems provides strong models for consideration of such effects in human and mouse genetics.

Animals↗

PubMed2001

Epigenetic developmental mechanisms in plants: molecules and targets of plant epigenetic regulation.

Genetic approaches to understanding the role of epigenetic regulation of gene expression in plants and its mechanisms have revealed several new components. Rapidly accumulating information from other eukaryotes provides complementary knowledge with important implications for plant research. Comparison of epigenetic events across species is proving critical for defining the mechanisms and functions of epigenetic modification, including those specific to plants.

Chromatin↗

PubMed2005

Epigenetic regulation of mammalian imprinted genes: from primary to functional imprints.

Parental genomic imprinting was discovered in mammals some 20 years ago. This phenomenon, crucial for normal development, rapidly became a key to understanding epigenetic regulation of mammalian gene expression. In this chapter we present a general overview of the field and describe in detail the 'imprinting cycle'. We provide selected examples that recapitulate our current knowledge of epigenetic regulation at imprinted loci. These epigenetic mechanisms lead to the stable repression of imprinted genes on one parental allele by interfering with 'formatting' for gene expression that usually occurs on expressed alleles. From this perspective, genomic imprinting remarkably illustrates the complexity of the epigenetic mechanisms involved in the control of gene expression in mammals.

Animals↗

PubMed2005

Human embryonic stem cells as a model for studying epigenetic regulation during early development.

In order to exploit the exceptional potential of human embryonic stem cells (hESCs) in cell-replacement therapies, the genetic and epigenetic factors controlling early human development must be better defined. Limitations in human embryonic material restrict the scale of studies that can be performed, and therefore an in vitro model in which to study epigenetic regulation in human preimplantation cell types would be desirable. HESCs could provide such a model, but since they are derived from a stage in mammalian development when the genome is undergoing global epigenetic remodelling, it is unclear whether their epigenetic status would be stable or subject to variation. Herein, we discuss recent work that examines allele-specific imprinted gene expression and methylation patterns, thereby demonstrating that hESCs maintain a substantial degree of epigenetic stability during culture. Therefore, we suggest that hESCs could provide a model for studying epigenetic regulation during the early stages of human cellular pluripotency and differentiation. Furthermore, we propose specific experiments using such a model to address important questions pertaining to epigenetic mechanisms of certain human disorders.

Animals↗

PubMed2001

Protein-coding genes are epigenetically regulated in Arabidopsis polyploids.

The fate of redundant genes resulting from genome duplication is poorly understood. Previous studies indicated that ribosomal RNA genes from one parental origin are epigenetically silenced during interspecific hybridization or polyploidization. Regulatory mechanisms for protein-coding genes in polyploid genomes are unknown, partly because of difficulty in studying expression patterns of homologous genes. Here we apply amplified fragment length polymorphism (AFLP)-cDNA display to perform a genome-wide screen for orthologous genes silenced in Arabidopsis suecica, an allotetraploid derived from Arabidopsis thaliana and Cardaminopsis arenosa. We identified ten genes that are silenced from either A. thaliana or C. arenosa origin in A. suecica and located in four of the five A. thaliana chromosomes. These genes represent a variety of RNA and predicted proteins including four transcription factors such as TCP3. The silenced genes in the vicinity of TCP3 are hypermethylated and reactivated by blocking DNA methylation, suggesting epigenetic regulation is involved in the expression of orthologous genes in polyploid genomes. Compared with classic genetic mutations, epigenetic regulation may be advantageous for selection and adaptation of polyploid species during evolution and development.

Arabidopsis↗