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At least 1,099 records · Page 61Linked to original sources
PubMed2006

Patterning of Arabidopsis epidermal cells: epigenetic factors regulate the complex epidermal cell fate pathway.

Cell fate determination in the Arabidopsis epidermis has been extensively studied for over a decade. Epidermal cells become either trichoblasts (hair-forming cells) or atrichoblasts (non-hair-forming cells). In Arabidopsis, two types of trichoblasts are formed in defined patterns: trichomes and root hairs. Both cell types are specified through the action of a common set of transcriptional regulators that define cell pattern. Recent studies also characterize epigenetic factors in the determination of cell fate in the root, suggesting a default pattern for epidermal cell fate that can be overridden by environmental stimuli. These results reveal how plant cell developmental plasticity is controlled at the molecular level.

Arabidopsis↗
PubMed2026

The Jumonji C domain-containing proteins GmJMJ19 and GmJMJ20 link florigen signaling with epigenetic regulation of photoperiodic flowering and post-flowering plant height in soybean.

Soybean (Glycine max) is a photoperiod-sensitive legume whose latitudinal adaptation depends on the precise control of flowering time and plant height. Histone demethylases of the JmjC domain-containing (JMJ) protein family have been implicated in these processes across plant species, but their specific roles in soybean remain largely unexplored. Here, we identify soybean GmJMJ19 and GmJMJ20, two closely related JMJD5/KDM8 orthologs, as master epigenetic regulators that coordinately control both photoperiodic flowering and post-flowering plant height. Both genes exhibit intrinsic, rhythmic expression peaking at ZT12, and their encoded proteins physically interact with the florigen proteins FT2a and FT5a. Loss-of-function mutants display delayed flowering under long days (LDs) and increased plant height under both LDs and short days (SDs), whereas overexpression phenocopies the mutant flowering phenotype, indicating revealing a critical dosage requirement for proper function. Mechanistically, GmJMJ19 and GmJMJ20 are recruited by the FT/FD transcriptional complex to directly activate AP1a and AP1c expression through chromatin modulation. Population genomic analyses reveal distinct selection signatures: GmJMJ19 underwent sustained directional selection during cultivation, whereas GmJMJ20 experienced an early domestication sweep with limited subsequent change. Haplotype analysis identifies coordinated latitudinal clines, with the JMJ19H1/JMJ20H1 combination predominating at high latitudes to promote early flowering and limit height, while JMJ19H2/JMJ20H2 and wild JMJ19H3/JMJ20H3 alleles prevail at low latitudes, conferring later flowering and increased height. Collectively, our findings establish GmJMJ19 and GmJMJ20 as central chromatin regulators linking florigen signaling to downstream target expression and provide valuable allelic resources for breeding regionally adapted soybean varieties across a wide range of latitudinal environments.

Histone modulation↗
PubMed2005

Epigenetic abnormalities of the mouse paternal zygotic genome associated with microinsemination of round spermatids.

Although round spermatid injection can be used to create progeny for males who do not produce mature sperm, the rate of successful embryogenesis after such procedures is significantly lower than that for similar procedures using mature spermatozoa. The mechanisms underlying this difference are unknown. In this study, we demonstrate that, unlike the normal paternal genome, the paternal zygotic genome derived from a round spermatid is highly remethylated before first mitosis after demethylation. Genomes from elongated spermatids exhibited an intermediate level of DNA methylation, between those of round spermatids and mature spermatozoa, suggesting that the male germ cell acquires the ability to maintain its undermethylated state in the paternal zygotic genome during this phase of spermiogenesis. In addition, treatment of zygotes with trichostatin A led to a significant reduction in DNA methylation, specifically in the spermatid-derived paternal genome, except for the pericentromeric regions enriched by trimethylation of Lys9 of histone H3. These data provide insight into epigenetic errors that may be associated with the poor development of embryos generated from immature spermatozoa.

Animals↗
PubMed2006

Epigenetic discrimination by mouse metaphase II oocytes mediates asymmetric chromatin remodeling independently of meiotic exit.

In mammalian fertilization, paternal chromatin is exhaustively remodeled, yet the maternal contribution to this process is unknown. To address this, we prevented the induction of meiotic exit by spermatozoa and examined sperm chromatin remodeling in metaphase II (mII) oocytes. Methylation of paternal H3-K4 and H3-K9 remained low, unlike maternal H3, although paternal H3-K4 methylation increased in zygotes. Thus, mII cytoplasm can sustain epigenetic asymmetry in a cell-cycle dependent manner. Paternal genomic DNA underwent oocyte-mediated cytosine demethylation and acquired maternally-derived K12-acetylated H4 (AcH4-K12) independently of microtubule assembly and maternal chromatin. AcH4-K12 persisted without typical maturation-associated deacetylation, irrespective of paternal pan-genomic cytosine methylation. Contrastingly, somatic cell nuclei underwent rapid H4 deacetylation; sperm and somatic chromatin exhibited asymmetric AcH4-K12 dynamics simultaneously within the same mII oocyte. Inhibition of somatic histone deacetylation revealed endogenous histone acetyl transferase activity. Oocytes thus specify the histone acetylation status of given nuclei by differentially targeting histone deacetylase and acetyl transferase activities. Asymmetric H4 acetylation during and immediately after fertilization was dispensable for development when both parental chromatin sets were hyperacetylated. These studies delineate non-zygotic chromatin remodeling and suggest a powerful model with which to study de novo genomic reprogramming.

Acetylation↗
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↗
PubMed2007

Histone acetyltransferase p300 modulates gene expression in an epigenetic manner at high blood alcohol levels.

When rats are fed ethanol intragastrically at a constant rate for 1 month, the urinary alcohol level (UAL) cycles over 7-9 day intervals. At the peak UAL, the liver is hypoxic shifting the redox state to a reduced rate. Microarray analysis done on livers at the UAL peaks shows changes in approximately 1300 gene expression compared to the pair-fed controls. To determine the mechanism of the gene expression changes, histone acetylation regulation was investigated in liver nuclear extracts at the peaks and troughs of the UAL and their pair-fed controls. No change occurred in SirT-1. P300, a histone acetyltransferase (HAT), which acetylates histone H3 on lysine 9, was increased at the peaks. Histone 3 acetylated at lysine 9 was also increased at the peaks. This indicates that the up regulated genes at the UAL peaks resulted from an increase in p300 transcription regulation, epigenetically. P300 activates transcription of numerous genes in response to signal transcription factors such as H1F 1alpha, increased in the nucleus at UAL peaks. Signal transduction pathways, such as NFkappaB, AP-1, ERK, JNK, and p38 were not increased at the peaks. beta-Catenin was increased in the nuclear extract at the UAL troughs, where increased gene expression was absent. The increase in gene expression at the peaks was due, in part, to increased acetylation of histone 3 at lysine 9.

Acetylation↗
PubMed2004

A NotI-EcoRV promoter library for studies of genetic and epigenetic alterations in mouse models of human malignancies.

Aberrant promoter methylation and associated chromatin changes are primarily studied in human malignancies. Thus far, mouse models for human cancer have been rarely utilized to study the role of DNA methylation in tumor onset and progression. It would be advantageous to use mouse tumor models to a greater extent to study the role and mechanism of DNA methylation in cancer because mouse models allow manipulation of the genome, study of samples/populations with a homogeneous genetic background, the possibility of modulating gene expression in vivo, the statistical power of using large numbers of tumor samples, access to various tumor stages, and the possibility of preclinical trials. Therefore, it is likely that the mouse will emerge as an increasingly utilized model to study DNA methylation in cancer. To foster the use of mouse models, we developed an arrayed mouse NotI-EcoRV genomic library, with clones from three commonly used mouse strains (129SvIMJ, FVB/NJ, and C57BL/6J). A total of 23,040 clones representing an estimated three- to fourfold coverage of the mouse genome were arrayed in 60 x 384-well plates. We developed restriction landmark genomic scanning (RLGS) mixing gels with 32 plates to enable the cloning of methylated sequences from RLGS profiles run with NotI-EcoRV-HinfI. RLGS was used to study aberrant methylation in two mouse models that overexpressed IL-15 or c-Myc and developed either T/NK-cell leukemia or T-cell lymphomas, respectively. Careful analysis of 198 sequences showed that 188 (94.9%) identified CpG-island sequences, 132 sequences (66.7%) had homology to the 5' regions of known genes or mRNAs, and all 132 NotI-EcoRV clones were located at the same CpG islands with the predicted promoter sequences. We have also developed a modified pGL3-based luciferase vector that now contains the NotI, AscI, and EcoRV restriction sites and allows the rapid cloning of NotI-EcoRV library fragments in both orientations. Luciferase assays using NotI-EcoRV clones confirmed that the library is enriched for promoter sequences. Thus, this library will support future genetic and epigenetic studies in mouse models.

Animals↗
PubMed2004

Epigenetic and genetic alternation of PTEN in cervical neoplasm.

OBJECTIVES: We studied the role of epigenetic and genetic changes of PTEN in the development of squamous cell carcinoma (SCC) of the uterine cervix and their value as a prognostic factor. METHODS: Ten high-grade cervical intraepithelial neoplasia (CIN-H) and 62 SCC tissues were used in this study. Microdissection was performed before loss of PTEN function through methylation of promoter CpG islands, deletion and mutation were studied. The findings were verified with PTEN protein expression and correlated with clinicopathologic information. RESULTS: PTEN mutation assessed by single-strand conformation polymorphism (PCR-SSCP) was not noted in any of the 62 SCC. Loss of heterozygosity (LOH) was only seen in eight SCC. PTEN promoter methylation was detected in 40% (4/10) of CIN-H and 58% (36/62) of SCC specimens. Loss of PTEN protein expression was associated with methylation of PTEN. PTEN methylation was not related to patient age, tumor grade or stage. Patients with persistent disease or who died of disease had a significantly higher percentage of PTEN methylation than those without evidence of recurrence. Multivariate Cox regression models confirmed PTEN was an important significant predictor both for total and disease-free survival after controlling age, pathologic grade and clinical stage. CONCLUSIONS: PTEN methylation and loss of PTEN expression are early events in the development of cervical cancer and may have prognostic significance.

Adult↗
PubMed2000

Epigenetic PTEN silencing in malignant melanomas without PTEN mutation.

A tumor suppressor gene at 10q 23.3, designated PTEN, encoding a dual specificity phosphatase with lipid and protein phosphatase activity, has been shown to play an important role in the pathogenesis of a variety of human cancers. Germline mutations in PTEN cause Cowden syndrome (CS), which is characterized by multiple hamartomas and a high risk of breast and thyroid cancers. Frequent loss of heterozygosity at 10q is found in both early and advanced-stage sporadic melanomas; however, mutations or deletions in PTEN are detected mainly in melanoma cell lines. In this study, we examined PTEN expression in 34 unselected sporadic melanomas (4 primary melanomas, 30 metastases) using immunohistochemistry and correlated this with the results of structural studies of this gene. Immunostaining of 34 melanoma samples revealed no PTEN expression in 5 (15%) and low PTEN expression in 17 (50%), whereas the rest of the tumors (35%) had high levels of expression. Hemizygous deletion was found in 32% of the tumors but neither intragenic PTEN mutation nor biallelic deletion was found in any of the samples. Of the 5 melanomas showing no PTEN expression, 4 had no mutation or deletion of PTEN. Of the 13 tumors having weak PTEN immunoreactivity and informative loss of heterozygosity results, 6 had evidence of hemizygous allelic loss of PTEN while the remaining 7 had intact PTEN. These results strongly support PTEN as a major tumor suppressor on 10q involved in melanoma tumorigenesis and suggest an epigenetic mechanism of biallelic functional inactivation not previously observed in other cancers where PTEN might be involved.

DNA Mutational Analysis↗
PubMed2000

Genetic and epigenetic changes in human epithelial cells immortalized by telomerase.

Exogenous expression of hTERT, the catalytic component of telomerase, is sufficient for the immortalization of human fibroblasts but insufficient for the immortalization of human foreskin keratinocytes (HFKs) and human mammary epithelial cells (HMECs). These latter cell types can overcome senescence by coexpression of hTERT and human papillomavirus (HPV) E7 or by expression of hTERT and loss of p16(INK4a) expression, indicating that the retinoblastoma (Rb) pathway, along with a telomere maintenance pathway, plays a role in determining the life span of epithelial cells. In this study, we further characterize hTERT-immortalized HFKs and human adenoid epithelial cells (HAKs) for genotypic and phenotypic alterations that are associated with immortalization. Of five hTERT-immortalized HFK and HAK cell lines examined, four exhibited repression of p16(INK4a) expression by promoter methylation or specific large-scale deletion of chromosome 9p, the location of p16(INK4a). Interestingly, one cell line exhibited complete down-regulation of expression of p14(ARF), with only slight down-regulation of expression of p16(INK4a). Yet, all of the immortal cells lines exhibited hyperphosphorylated Rb. Cytogenetic analysis revealed clonal chromosome aberrations in three of the five cell lines. All of the cell lines retained a growth block response with the expression of mutant ras. When grown on organotypic raft cultures, however, the hTERT-immortalized cells exhibited a maturation delay on terminal differentiation. Our results indicate that immortalization of epithelial cells may require both activation of telomerase and other genetic and/or epigenetic alterations that abrogate normal differentiation.

Animals↗
PubMed2000

Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers.

Microsatellite instability (MSI) is a hallmark of hereditary nonpolyposis colorectal cancer, and in these patients, results from inherited defects in DNA mismatch repair genes, mostly MSH2 and MLH1. MSI also occurs in 15% of sporadic colorectal cancers, but in these tumors, its basis is less well characterized. We investigated 46 sporadic MSI+ colorectal cancers for changes in MSH2 and MLH1 protein expression, followed by the analysis of somatic mutation, loss of heterozygosity (LOH), and promoter hypermethylation as possible underlying defects. Most cases (36/46, 78%) showed lost or reduced MLH1 expression. Among these, a majority (83%) was associated with MLH1 promoter hypermethylation, whereas the rates of LOH and somatic mutation of MLH1 were 24% and 13%, respectively. Hypermethylation and LOH were inversely correlated, suggesting that they had alternative functions in the inactivation of MLH1. MSH2 expression was lost in 7/46 (15%), and of these, 2 (29%) showed LOH and/or somatic mutation of MSH2. We conclude that most sporadic MSI+ colorectal cancers have an MLH1-associated etiology and that epigenetic modification is a major mechanism of MLH1 inactivation. Moreover, we found a significantly lower prevalence for MLH1 promoter hypermethylation in hereditary nonpolyposis colorectal cancer tumors with MLH1 germline mutations (12/26, 46%), which might explain some differences that are known to occur in the clinicopathological characteristics and tumorigenic pathways between sporadic and hereditary MSI+ colorectal cancers.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Epigenetic control of mouse receptor activator of NF-kappa B ligand gene expression.

Receptor activator of NF-kappa B ligand (RANKL) is a membrane-bound signal transducer requisite for differentiation and maintenance of osteoclasts. RANKL expression on stromal/osteoblastic cells is tightly regulated to maintain physiological serum calcium levels and bone mass. These stromal/osteoblastic cells, however, comprise a rather heterogeneous population ranging from immature mesenchymal cells to mature osteoblasts and also respond differently to bone resorptive stimuli. In the mouse coculture system, we also have demonstrated the passage-dependent difference of cultured mouse stromal cells in supporting osteoclastogenesis due to altered RANKL gene expression. To address the issue of what molecular mechanism gives the diversity of RANKL gene expression to stromal/osteoblastic cells, we characterized the mouse RANKL gene promoter that contains two CpG clustering regions; one around the transcription start site, and the other downstream of the vitamin D response element (VDRE). Using earlier- and later-passage mouse ST2 cells, we analyzed the CpG methylation status by sodium bisulfite mapping and found that CpG loci around the transcription start site (-66/+246) were predominantly methylated in later-passage ST2 cells. Moreover, earlier- and later-passage ST2 cells transfected with a RANKL promoter construct showed the same steady-state level of luciferase activity and of the inducible effect of 1,25(OH)(2)D(3). Furthermore, the introduction of methylation to the promoter construct silenced promoter activity. The results suggest that CpG methylation around the transcription start site of the mouse RANKL gene is an important epigenetic event, and that its heterogeneity might cause the diversity of the stromal/osteoblastic cells in RANKL gene expression.

Animals↗
PubMed2003

Tissue-specific activity of the proximal human calcitonin receptor promoter is mediated by Sp1 and an epigenetic phenomenon.

To identify cis-acting sequences transcriptionally regulating the human calcitonin receptor (hCTR) gene, hCTR promoter/luciferase gene constructs were transiently or stably transfected into hCTR-positive and -negative cell lines. Luciferase assays demonstrated that the proximal hCTR promoter (hCTRP1) was transcriptionally active in all cell lines tested. High-level hCTRP1 activity depended on an 11 bp Sp1/Sp3 binding site. Electrophoretic mobility shift assay showed that this region bound the transcription factors Sp1 and Sp3. We further showed that hCTRP1 was strongly activated by the 11 bp Sp1/Sp3 binding site in hCTRP1/luciferase-, Sp1-transfected Drosophila S2 cells. Bisulphite-mediated sequencing of genomic DNA from hCTR-expressing and -non-expressing cell lines demonstrated that the endogenous hCTRP1 was hypomethylated in all cell lines tested. These results suggest that the hCTRP1 is activated by the tissue-ubiquitous transcription factor Sp1 and that an epigenetic process unrelated to CpG methylation represses its activity in hCTR-negative tissues.

Animals↗
PubMed2003

Epigenetic and genetic alterations in duodenal carcinomas are distinct from biliary and ampullary carcinomas.

BACKGROUND & AIMS: Carcinomas of the extrahepatic bile ducts, ampulla of Vater, and duodenum are uncommon, and their epigenetic and genetic alterations are not well characterized. METHODS: We therefore compared the methylation profile and genetic alterations in 18 extrahepatic biliary, 9 ampullary, and 12 duodenal carcinomas. We evaluated methylation at p16, p14, and human Mut L homologue (hMLH1) by methylation- specific PCR (MSP), and at cyclooxygenase 2 (COX2), O(6)-methyl-guanine methyltransferase (MGMT), estrogen receptor (ER), retinoic acid receptor beta 2 (RAR beta), and T-type calcium channel (CACNA1G) genes, and methylated in tumor 1 (MINT1), MINT2, MINT25, MINT27, and MINT31 loci by combined bisulfite restriction analysis (COBRA); mutation of K-ras, p53, p16, and p14 genes by sequencing; loss of heterozygosity of chromosome 9p; and microsatellite instability (MSI). RESULTS: Duodenal carcinomas were methylated more frequently or had increased methylation densities than biliary carcinomas at p14 (P = 0.04), hMLH1 (P = 0.04), MGMT (P = 0.01), MINT1 (P = 0.01), MINT25 (P = 0.01), MINT27 (P = 0.001), RAR beta (P = 0.03), and ER (P = 0.001), and than ampullary carcinomas at RAR beta (P = 0.02) and ER (P = 0.03). In contrast, the methylation profiles of biliary and ampullary carcinomas were not statistically different. Simultaneous methylation of 3 or more CpG islands (CpG island methylator phenotype-high) was more common in duodenal cancers (P = 0.004). MGMT methylation was associated with G-to-A mutation in K-ras (P = 0.006), and hMLH1 methylation was associated with MSI-high (P = 0.01). CONCLUSIONS: Our findings indicate that the methylation profile and genetic alterations of duodenal carcinomas are distinct from biliary and ampullary carcinomas, and that tumor-specific methylation is associated with gene mutation and MSI.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Epigenetics and epimutagens: some new perspectives on cancer, germ line effects and endocrine disrupters.

It is known that a variety of chemicals, including certain base analogues and reactive oxygen species, can alter the phenotypes of mammalian cells epigenetically, i.e., without changing their DNA sequence information in any way. The implications of such findings are not trivial, but do not seem to have been the focus of a great deal of attention amongst mutation researchers to date. In part this may be a reflection of the confused state of terminology in the chemical carcinogenesis research area and in part may signal a reluctance on the part of many of us to come to terms with the idea of heritable non-sequence changes to DNA molecules. In this review, some of the most obvious outcomes of spontaneous and induced epimutagenic change for human carcinogenesis and germ line inheritance are discussed, and an attempt is made to place the so-called endocrine disrupters in a context in which their modes of action may be more readily analysed and integrated into the broader chemical hazard framework.

Animals↗
PubMed1998

Epigenetic control of programmed cell death: inhibition by 5-azacytidine of 1,25-dihydroxyvitamin D3-induced programmed cell death in C6.9 glioma cells.

In mammalian DNA cytosine methylation occurs specifically at CpG dinucleotide. Although the full array of function of DNA methylation is yet to be elucidated, it is well established that DNA methylation is an important mechanism involved in gene expression, DNA replication and cancer. Rat glioma C6.9 cells undergo programmed cell death (PCD) after treatment with 1,25-dihydroxyvitamin D3 (1,25-D3). Hence, these cells were used to study whether DNA methylation was involved in the control of PCD. We found that 1,25-D3-mediated PCD of C6.9 cells was suppressed by exposure of the cells to the DNA demethylating agents 5-azacytidine (5-AzaC) and 5-aza-2'-deoxycytidine. This effect remains detectable several cell divisions following removal of 5-AzaC and, therefore, involves DNA methylation as an epigenetic regulatory mechanism of PCD. Accordingly, internucleosomal fragmentation, a feature of apoptosis that is detected in 1,25-D3-treated cells, is no longer observable after treatment of these cells with 5-AzaC. However, 5-AzaC does not totally suppress the responsiveness of C6.9 cells to 1,25-D3 since the induction of the c-myc gene remains unaffected. These results suggest that a change in DNA methylation pattern could suppress 1,25-D3-mediated PCD through the expression of previously hypermethylated genes such as proto-oncogenes with death-repressor activity, endogenous virus sequences or even genes inducing change in the differentiated state of these cells.

Animals↗
PubMed2003

Epigenetic theories of cancer initiation.

I argue that carcinogenic insults injure many cells rather than mutate a few. This results from evidence that such insults convert too many cells to a precancerous state and that too many of the converted cells then revert to plausibly involve mutation and its repair; from evidence that the delays between such insults and chemically demonstrable mutations are long enough to easily allow nonmutational mechanisms to work; from evidence that even ionizing radiation first acts on the cytoplasm and mainly affects cells unhit by it; from the fact that such insults induce proto-oncogene expression far too quickly to do so by mutation; and from the fact that fusions of various cells and cell parts show that the tumorous or nontumorous nature of the product depends on its cytoplasmic rather than its nuclear component. I further argue that reduced DNA methylation, modifications of the histone code, and tissue disorganization are the three main mechanisms of epigenetic cancer initiation. Hypomethylation would result from DNA excision repair. Moreover, a methyl-deficient diet is carcinogenic and demethylation is also known to be carcinogenic via the histone code. Finally, I strongly argue for tissue disorganization as a mechanism of cancer initiation. This results from evidence that skin carcinogens disrupt the dermal/epidermal connection and from the fact that tumorigens swiftly disrupt gap junctions, as well as from evidence that such disruption is tumorigenic.

Animals↗