'; ?> geneimprint : Hot off the Press http://www.geneimprint.com/site/hot-off-the-press Daily listing of the most recent articles in epigenetics and imprinting, collected from the PubMed database. en-us Sat, 25 May 2013 12:28:15 PDT Sat, 25 May 2013 12:28:15 PDT jirtle@radonc.duke.edu james001@jirtle.com Epigenetic regulation of placental endocrine lineages and complications of pregnancy. John RM
Biochem Soc Trans (Jun 2013)

A defining feature of mammals is the development in utero of the fetus supported by the constant flow of nutrients from the mother obtained via a specialized organ: the placenta. The placenta is also a major endocrine organ that synthesizes vast quantities of hormones and cytokines to instruct both maternal and fetal physiology. Nearly 20 years ago, David Haig and colleagues proposed that placental hormones were likely targets of the epigenetic process of genomic imprinting in response to the genetic conflicts imposed by in utero development [Haig (1993) Q. Rev. Biol. 68, 495-532]. There are two simple mechanisms through which genomic imprinting could regulate placental hormones. First, imprints could directly switch on or off alleles of specific genes. Secondly, imprinted genes could alter the expression of placental hormones by regulating the development of placental endocrine lineages. In mice, the placental hormones are synthesized in the trophoblast giant cells and spongiotrophoblast cells of the mature placenta. In the present article, I review the functional role of imprinted genes in regulating these endocrine lineages, which lends support to Haig's original hypothesis. I also discuss how imprinting defects in the placenta may adversely affect the health of the fetus and its mother during pregnancy and beyond.]]> Thu, 23 May 2013 00:00:00 PDT Growth hormone receptor (GHR) gene polymorphism and prader-willi syndrome. Butler MG, Roberts J, Hayes J, Tan X, Manzardo AM
Am J Med Genet A (May 2013)

Prader-Willi syndrome (PWS) is a genomic imprinting disorder due to loss of paternally expressed genes in the 15q11-q13 region and characterized by hypotonia, a poor suck, failure to thrive, hypogonadism/hypogenitalism, growth hormone deficiency, learning, and behavioral problems and hyperphagia leading to early childhood obesity. Growth hormone acts as a ligand for the growth hormone receptor (GHR) coded by a gene polymorphic for an exon-3 deletion (d3) seen in about 50% of Caucasians and associated with an increased response to growth hormone (GH) therapy. We examined 69 individuals with PWS (average age ± SD = 20.1 ± 12.8 year). The GHR allele distribution in our PWS subjects was similar to reported data in the literature with no gender or PWS genetic subtype differences. A negative correlation was found with age for height standard deviational scores and a positive correlation with age for weight and BMI for non-GH treated PWS subjects. Adjusting for effects of age and gender, individuals with PWS and the d3/d3 allele showed a significant increase in BMI compared with those having the full length (fl) allele. In addition, 12 infants and children with PWS were examined when growth and GH data were available before and during GH treatment. A significant increase in growth rate (1.7 times) was noted in the presence of the d3 allele (fl/fl = 0.87 cm/month; fl/d3 or d3/d3 = 1.5 cm/month; P < 0.05). The presence of the d3 allele and its impact on growth and medical care of individuals with PWS while on GH therapy should be further investigated. © 2013 Wiley Periodicals, Inc.]]> Wed, 22 May 2013 00:00:00 PDT Equity in Public Health: An Epigenetic Perspective. Stapleton G, Schröder-Bäck P, Townend D
Public Health Genomics (May 2013)

Evidence emerging from the study of epigenetics and epigenomics challenges notions of health by enhancing understanding of disease etiologies and improving awareness of new health risks. New paradigms arising from epigenetic and epigenomic research present challenging cases through which to debate theories of justice in health because they expand the concept of health and, controversially, place value on what was previously assumed to be 'healthy' individual variance. Discoveries of the dynamic nature of the epigenome and its variable sensitivity towards change in numerous phenomena add further complexity to the assessment of health inequalities. Such evidence can cast doubt on perceptions of justice in health, which in turn raises questions over the suitability of actions taken in pursuit of equity. This article discusses how recent developments in epigenetics and epigenomics may impact upon assessments of equity in health. A review of literature discussing possible health risks associated with acquired yet heritable epigenetic variance is used to highlight the diversity of possible pathways through which health may be influenced. From this context, the consideration of health risk with respect to epigenetics, it is argued, demands a more inclusive concept of health when used in discussions of inequities.]]> Tue, 21 May 2013 00:00:00 PDT The role of imprinted genes in humans. Ishida M, Moore GE
Mol Aspects Med ()

Genomic imprinting, a process of epigenetic modification which allows the gene to be expressed in a parent-of-origin specific manner, has an essential role in normal growth and development. Imprinting is found predominantly in placental mammals, and has potentially evolved as a mechanism to balance parental resource allocation to the offspring. Therefore, genetic and epigenetic disruptions which alter the specific dosage of imprinted genes can lead to various developmental abnormalities often associated with fetal growth and neurological behaviour. Over the past 20years since the first imprinted gene was discovered, many different mechanisms have been implicated in this special regulatory mode of gene expression. This review includes a brief summary of the current understanding of the key molecular events taking place during imprint establishment and maintenance in early embryos, and their relationship to epigenetic disruptions seen in imprinting disorders. Genetic and epigenetic causes of eight recognised imprinting disorders including Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS), and also their association with Assisted reproductive technology (ART) will be discussed. Finally, the role of imprinted genes in fetal growth will be explored by investigating their relationship to a common growth disorder, intrauterine growth restriction (IUGR) and also their potential role in regulating normal growth variation.]]> Mon, 20 May 2013 00:00:00 PDT Measuring the exposome: A powerful basis for evaluating environmental exposures and cancer risk. Wild CP, Scalbert A, Herceg Z
Environ Mol Mutagen (May 2013)

Advances in laboratory sciences offer much in the challenge to unravel the complex etiology of cancer and to therefore provide an evidence-base for prevention. One area where improved measurements are particularly important to epidemiology is exposure assessment; this requirement has been highlighted through the concept of the exposome. In addition, the ability to observe genetic and epigenetic alterations in individuals exposed to putative risk factors also affords an opportunity to elucidate underlying mechanisms of carcinogenesis, which in turn may allow earlier detection and more refined molecular classification of disease. In this context the application of omics technologies to large population-based studies and their associated biobanks raise exciting new avenues of research. This review considers the areas of genomics, transcriptomics, epigenomics and metabolomics and the evidence to date that people exposed to well-defined factors (for example, tobacco, diet, occupational exposures, environmental pollutants) have specific omics profiles. Although in their early stages of development these approaches show promising evidence of distinct exposure-derived biological effects and indicate molecular pathways that may be particularly relevant to the carcinogenic process subsequent to environmental and lifestyle exposures. Such an interdisciplinary approach is vital if the full benefits of advances in laboratory sciences and investments in large-scale prospective cohort studies are to be realized in relation to cancer prevention. Environ. Mol. Mutagen., 2013. © 2013 Wiley Periodicals, Inc.]]> Fri, 17 May 2013 00:00:00 PDT Cancer control and prevention: nutrition and epigenetics. Verma M
Curr Opin Clin Nutr Metab Care (May 2013)

PURPOSE OF REVIEW: To evaluate recent developments in nutritional epigenomics and related challenges, opportunities, and implications for cancer control and prevention. RECENT FINDINGS: Cancer is one of the leading causes of death worldwide, and understanding the factors that contribute to cancer development may facilitate the development of strategies for cancer prevention and control. Cancer development involves genetic and epigenetic alterations. Genetic marks are permanent, whereas epigenetic marks are dynamic, change with age, and are influenced by the external environment. Thus, epigenetics provides a link between the environment, diet, and cancer development. Proper food selection is imperative for better health and to avoid cancer and other diseases. Nutrients either contribute directly to cancer prevention or support the repair of genomic and epigenomic damage caused by exposure to cancer-causing agents such as toxins, free radicals, radiation, and infectious agents. Nutritional epigenomics provides an opportunity for cancer prevention because selected nutrients have the potential to reverse cancer-associated epigenetic marks in different tumor types. A number of natural foods and their bioactive components have been shown to have methylation-inhibitory and deacetylation-inhibitory properties. SUMMARY: Natural foods and bioactive food components have characteristics and functions that are similar to epigenetic inhibitors and therefore have potential in cancer control and prevention.]]> Thu, 16 May 2013 00:00:00 PDT The Battle of the Sexes over Seed Size: Support for Both Kinship Genomic Imprinting and Interlocus Contest Evolution. Willi Y
Am Nat (Jun 2013)

Abstract Outcrossing creates a venue for parental conflict. When one sex provides parental care to offspring fertilized by several partners, the nonproviding sex is under selection to maximally exploit the caring sex. The caring sex may counteradapt, and a coevolutionary arms race ensues. Genetic models of this conflict include the kinship theory of genomic imprinting (parent-of-origin-specific expression of maternal-care effectors) and interlocus conflict evolution (interaction between male selfish signals and female abatement). Predictions were tested by measuring the sizes of seeds produced by within-population crosses (diallel design) and between-population crosses in outcrossing and selfing populations of Arabidopsis lyrata. Within-population diallel crosses revealed substantial maternal variance in seed size in most populations. The comparison of between- and within-population crosses showed that seeds were larger when pollen came from another outcrossing population than when pollen came from a selfing or the same population, supporting interlocus contest evolution between male selfish genes and female recognition genes. Evidence for kinship genomic imprinting came from complementary trait means of seed size in reciprocal between-population crosses independent of whether populations were predominantly selfing or outcrossing. Hence, both kinship genomic imprinting and interlocus contest are supported in outcrossing Arabidopsis, whereas only kinship genomic imprinting is important in selfing populations.]]> Tue, 14 May 2013 00:00:00 PDT Genomic imprinting effects of the x chromosome on brain morphology. Lepage JF, Hong DS, Mazaika PK, Raman M, Sheau K, Marzelli MJ, Hallmayer J, Reiss AL
J Neurosci (May 2013)

There is increasing evidence that genomic imprinting, a process by which certain genes are expressed in a parent-of-origin-specific manner, can influence neurogenetic and psychiatric manifestations. While some data suggest possible imprinting effects of the X chromosome on physical and cognitive characteristics in humans, there is no compelling evidence that X-linked imprinting affects brain morphology. To address this issue, we investigated regional cortical volume, thickness, and surface area in 27 healthy controls and 40 prepubescent girls with Turner syndrome (TS), a condition caused by the absence of one X chromosome. Of the young girls with TS, 23 inherited their X chromosome from their mother (X(m)) and 17 from their father (X(p)). Our results confirm the existence of significant differences in brain morphology between girls with TS and controls, and reveal the presence of a putative imprinting effect among the TS groups: girls with X(p) demonstrated thicker cortex than those with X(m) in the temporal regions bilaterally, while X(m) individuals showed bilateral enlargement of gray matter volume in the superior frontal regions compared with X(p). These data suggest the existence of imprinting effects of the X chromosome that influence both cortical thickness and volume during early brain development, and help to explain variability in cognitive and behavioral manifestations of TS with regard to the parental origin of the X chromosome.]]> Thu, 09 May 2013 00:00:00 PDT Genomic imprinting of the type 3 thyroid hormone deiodinase gene: Regulation and developmental implications. Charalambous M, Hernandez A
Biochim Biophys Acta (Jul 2013)

In recent years, findings in a number of animal and human models have ignited renewed interest in the type 3 deiodinase (D3), the main enzyme responsible for the inactivation of thyroid hormones. The induction of D3 in models of illness and injury has raised critical questions about the physiological significance of reduced thyroid hormone availability in those states. Phenotypes in transgenic mice lacking this enzyme also point to important developmental roles for D3. A critical determinant of D3 expression is genomic imprinting, an epigenetic phenomenon that regulates a small number of dosage-critical genes in the mammalian genome. The D3 gene (Dio3) is imprinted and preferentially expressed from one of the alleles in most tissues.]]> Wed, 08 May 2013 00:00:00 PDT Imprinted expression of genes and small RNA is associated with localized hypomethylation of the maternal genome in rice endosperm. Rodrigues JA, Ruan R, Nishimura T, Sharma MK, Sharma R, Ronald PC, Fischer RL, Zilberman D
Proc Natl Acad Sci U S A (May 2013)

Arabidopsis thaliana endosperm, a transient tissue that nourishes the embryo, exhibits extensive localized DNA demethylation on maternally inherited chromosomes. Demethylation mediates parent-of-origin-specific (imprinted) gene expression but is apparently unnecessary for the extensive accumulation of maternally biased small RNA (sRNA) molecules detected in seeds. Endosperm DNA in the distantly related monocots rice and maize is likewise locally hypomethylated, but whether this hypomethylation is generally parent-of-origin specific is unknown. Imprinted expression of sRNA also remains uninvestigated in monocot seeds. Here, we report high-coverage sequencing of the Kitaake rice cultivar that enabled us to show that localized hypomethylation in rice endosperm occurs solely on the maternal genome, preferring regions of high DNA accessibility. Maternally expressed imprinted genes are enriched for hypomethylation at putative promoter regions and transcriptional termini and paternally expressed genes at promoters and gene bodies, mirroring our recent results in A. thaliana. However, unlike in A. thaliana, rice endosperm sRNA populations are dominated by specific strong sRNA-producing loci, and imprinted 24-nt sRNAs are expressed from both parental genomes and correlate with hypomethylation. Overlaps between imprinted sRNA loci and imprinted genes expressed from opposite alleles suggest that sRNAs may regulate genomic imprinting. Whereas sRNAs in seedling tissues primarily originate from small class II (cut-and-paste) transposable elements, those in endosperm are more uniformly derived, including sequences from other transposon classes, as well as genic and intergenic regions. Our data indicate that the endosperm exhibits a unique pattern of sRNA expression and suggest that localized hypomethylation of maternal endosperm DNA is conserved in flowering plants.]]> Wed, 08 May 2013 00:00:00 PDT A data-driven approach to preprocessing Illumina 450K methylation array data. Pidsley R, Wong CC, Volta M, Lunnon K, Mill J, Schalkwyk LC
BMC Genomics (May 2013)

Background As the most stable and experimentally accessible epigenetic mark, DNA methylation is of great interest to the research community. The landscape of DNA methylation across tissues, through development and in disease pathogenesis is not yet well characterized. Thus there is a need for rapid and cost effective methods for assessing genome-wide levels of DNA methylation. The Illumina Infinium HumanMethylation450 (450K) BeadChip is a very useful addition to the available methods for DNA methylation analysis but its complex design, incorporating two different assay methods, requires careful consideration. Accordingly, several normalization schemes have been published.We have taken advantage of known DNA methylation patterns associated with genomic imprinting and X-chromosome inactivation (XCI), in addition to the performance of SNP genotyping assays present on the array, to derive three independent metrics which we use to test alternative schemes of correction and normalization. These metrics also have potential utility as quality scores for datasets.Results The standard index of DNA methylation at any specific CpG site is ß = M/(M + U + 100) where M and U are methylated and unmethylated signal intensities, respectively. Betas (ßs) calculated from raw signal intensities (the default GenomeStudio behavior) perform well, but using 11 methylomic datasets we demonstrate that quantile normalization methods produce marked improvement, even in highly consistent data, by all three metrics. The commonly used procedure of normalizing betas is inferior to the separate normalization of M and U, and it is also advantageous to normalize Type I and Type II assays separately. More elaborate manipulation of quantiles proves to be counterproductive.Conclusions Careful selection of preprocessing steps can minimize variance and thus improve statistical power, especially for the detection of the small absolute DNA methylation changes likely associated with complex disease phenotypes. For the convenience of the research community we have created a user-friendly R software package called wateRmelon, downloadable from bioConductor, compatible with the existing methylumi, minfi and IMA packages, that allows others to utilize the same normalization methods and data quality tests on 450K data.]]> Wed, 01 May 2013 00:00:00 PDT Stability of genomic imprinting in human induced pluripotent stem cells. Hiura H, Toyoda M, Okae H, Sakurai M, Miyauchi N, Sato A, Kiyokawa N, Okita H, Miyagawa Y, Akutsu H, Nishino K, Umezawa A, Arima T
BMC Genet (Apr 2013)

BACKGROUND: hiPSCs are generated through epigenetic reprogramming of somatic tissue. Genomic imprinting is an epigenetic phenomenon through which monoallelic gene expression is regulated in a parent-of-origin-specific manner. Reprogramming relies on the successful erasure of marks of differentiation while maintaining those required for genomic imprinting. Loss of imprinting (LOI), which occurs in many types of malignant tumors, would hinder the clinical application of hiPSCs. RESULTS: We examined the imprinting status, expression levels and DNA methylation status of eight imprinted genes in five independently generated hiPSCs. We found a low frequency of LOI in some lines. Where LOI was identified in an early passage cell line, we found that this was maintained through subsequent passages of the cells. Just as normal imprints are maintained in long-term culture, this work suggests that abnormal imprints are also stable in culture. CONCLUSIONS: Analysis of genomic imprints in hiPSCs is a necessary safety step in regenerative medicine, with relevance both to the differentiation potential of these stem cells and also their potential tumorigenic properties.]]> Wed, 01 May 2013 00:00:00 PDT Abnormal methylation of KCNQ1OT1 and differential methylation of H19 imprinting control regions in human ICSI embryos. Khoueiry R, Ibala-Romdhane S, Al-Khtib M, Blachère T, Lornage J, Guérin JF, Lefèvre A
Zygote (May 2013)

Summary To evaluate the integrity of genomic imprinting in embryos that failed to develop normally following intracytoplasmic sperm injection (ICSI), we analysed the methylation profile of H19 and KCNQ1OT1 imprinting control regions, H19DMR and KvDMR1 respectively, in high-grade blastocysts and in embryos that exhibited developmental anomalies. Significant hypomethylation of KvDMR1 was specifically observed in 5/5 atypical blastocysts graded BC, which probably reflected the vulnerability of the imprint in the inner cell mass during the methylation remodelling phase in the early embryo. In addition, KvDMR1 was hypermethylated in 2/5 CC graded atypical blastocysts and in 2/8 embryos that exhibited developmental delay. H19DMR appeared differentially methylated in all groups of embryos. DNA methyltransfersase 1 (DNMT1) expression was similar in most of the tested embryos and could not account for the abnormal methylation patterns of KvDMR1 observed.]]> Tue, 23 Apr 2013 00:00:00 PDT Bridging epigenomics and complex disease: the basics. Teperino R, Lempradl A, Pospisilik JA
Cell Mol Life Sci (May 2013)

The DNA sequence largely defines gene expression and phenotype. However, it is becoming increasingly clear that an additional chromatin-based regulatory network imparts both stability and plasticity to genome output, modifying phenotype independently of the genetic blueprint. Indeed, alterations in this "epigenetic" control layer underlie, at least in part, the reason for monozygotic twins being discordant for disease. Functionally, this regulatory layer comprises post-translational modifications of DNA and histones, as well as small and large noncoding RNAs. Together these regulate gene expression by changing chromatin organization and DNA accessibility. Successive technological advances over the past decade have enabled researchers to map the chromatin state with increasing accuracy and comprehensiveness, catapulting genetic research into a genome-wide era. Here, aiming particularly at the genomics/epigenomics newcomer, we review the epigenetic basis that has helped drive the technological shift and how this progress is shaping our understanding of complex disease.]]> Fri, 12 Apr 2013 00:00:00 PDT Deciphering the epigenetic code: an overview of DNA methylation analysis methods. Umer M, Herceg Z
Antioxid Redox Signal (May 2013)

Methylation of cytosine in DNA is linked with gene regulation, and this has profound implications in development, normal biology, and disease conditions in many eukaryotic organisms. A wide range of methods and approaches exist for its identification, quantification, and mapping within the genome. While the earliest approaches were nonspecific and were at best useful for quantification of total methylated cytosines in the chunk of DNA, this field has seen considerable progress and development over the past decades. RECENT ADVANCES: Methods for DNA methylation analysis differ in their coverage and sensitivity, and the method of choice depends on the intended application and desired level of information. Potential results include global methyl cytosine content, degree of methylation at specific loci, or genome-wide methylation maps. Introduction of more advanced approaches to DNA methylation analysis, such as microarray platforms and massively parallel sequencing, has brought us closer to unveiling the whole methylome.]]> Thu, 11 Apr 2013 00:00:00 PDT State of genomics and epigenomics research in the perspective of HIV cure. Ciuffi A, Telenti A
Curr Opin HIV AIDS (May 2013)

One of the seven key scientific priorities identified in the road map on HIV cure research is to 'determine the host mechanisms that control HIV replication in the absence of therapy'. This review summarizes the recent work in genomics and in epigenetic control of viral replication that is relevant for this mission.]]> Thu, 11 Apr 2013 00:00:00 PDT Mitochondrial complex II and genomic imprinting in inheritance of paraganglioma tumors. Baysal BE
Biochim Biophys Acta (May 2013)

Germ line heterozygous mutations in the structural subunit genes of mitochondrial complex II (succinate dehydrogenase; SDH) and the regulatory gene SDHAF2 predispose to paraganglioma tumors which show constitutive activation of hypoxia inducible pathways. Mutations in SDHD and SDHAF2 cause highly penetrant multifocal tumor development after a paternal transmission, whereas maternal transmission rarely, if ever, leads to tumor development. This transmission pattern is consistent with genomic imprinting. Recent molecular evidence supports a model for tissue-specific imprinted regulation of the SDHD gene by a long range epigenetic mechanism. In addition, there is evidence of SDHB mRNA editing in peripheral blood mononuclear cells and long-term balancing selection operating on the SDHA gene. Regulation of SDH subunit expression by diverse epigenetic mechanisms implicates a crucial dosage-dependent role for SDH in oxygen homeostasis. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease.]]> Tue, 02 Apr 2013 00:00:00 PDT Epstein-Barr virus-induced epigenetic alterations following transient infection. Queen KJ, Shi M, Zhang F, Cvek U, Scott RS
Int J Cancer (May 2013)

Epstein-Barr virus (EBV) is a known tumor virus associated with an increasing array of malignancies; however, the association of the virus with certain malignancies is often erratic. To determine EBV's contributions to tumorigenesis in a setting of incomplete association, a transient model of infection was established where a clonal CCL185 carcinoma cell line infected with recombinant EBV was allowed to lose viral genomes by withdrawal of selection pressure. Global gene expression comparing EBV-negative, transiently infected clones to uninfected controls identified expression changes in more than 1,000 genes. Among downregulated genes, several genes known to be deoxyribonucleic acid (DNA) methylated in cancer were identified including E-cadherin and PYCARD. A cadherin switch, increased motility and enhanced cellular invasiveness present in EBV-positive cells were retained after viral loss, indicating an epigenetic effect. Repression of PYCARD expression was a result of increased promoter CpG methylation, whereas loss of E-cadherin expression after transient EBV infection did not correlate with increased DNA methylation of the E-cadherin promoter. Rather, repression of E-cadherin was consistent with the formation of a repressive chromatin state. Decreased histone 3 or 4 acetylation at the promoter and 5' end of the E-cadherin gene was observed in an EBV-negative, transiently infected clone relative to the uninfected controls. These results suggest that EBV can stably alter gene expression in a heritable fashion in formerly infected cells, whereas its own contribution to the oncogenic process is masked.]]> Tue, 19 Feb 2013 00:00:00 PST Histone deacetylases as targets for treatment of multiple diseases. Tang J, Yan H, Zhuang S
Clin Sci (Lond) (Jun 2013)

HDACs (histone deacetylases) are a group of enzymes that deacetylate histones as well as non-histone proteins. They are known as modulators of gene transcription and are associated with proliferation and differentiation of a variety of cell types and the pathogenesis of some diseases. Recently, HDACs have come to be considered crucial targets in various diseases, including cancer, interstitial fibrosis, autoimmune and inflammatory diseases, and metabolic disorders. Pharmacological inhibitors of HDACs have been used or tested to treat those diseases. In the present review, we will examine the application of HDAC inhibitors in a variety of diseases with the focus on their effects of anti-cancer, fibrosis, anti-inflammatory, immunomodulatory activity and regulating metabolic disorders.]]> Mon, 18 Feb 2013 00:00:00 PST Efficacy of decitabine-loaded nanogels in overcoming cancer drug resistance is mediated via sustained DNA methyltransferase 1 (DNMT1) depletion. Vijayaraghavalu S, Labhasetwar V
Cancer Lett (Apr 2013)

DNA methyltransferase 1 (DNMT1) promotes DNA methylation to maintain cancer drug resistance. The epigenetic drug, decitabine (DAC) is a potent hypomethylating agent, but its effect is transient because of its instability. We tested the efficacy of DAC-loaded nanogels in doxorubicin-resistant breast cancer cells, DAC-resistant melanoma cells, and leukemia cells. DAC in nanogel sustained DNMT1 depletion, prolonged cell arrest in the G2/M cell-cycle phase, and significantly enhanced antiproliferative effect of DAC. The efficacy of DAC-loaded nanogels was more significant in resistant than sensitive cells. Our data suggest that effective delivery of DAC and prolonged DNMT1 depletion are critical to overcoming drug resistance.]]> Wed, 13 Feb 2013 00:00:00 PST