PLoS ONE: Why I Changed My Mind


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Longtime readers may remember a couple years ago when I did a post subtly criticizing the relatively new journal PLoS ONE, saying that it was not much more than a repository for rejected papers from the more selective PLoS journals, such as PLoS Biology and PLoS Genetics.  Immediately after, I took flack some of the more senior people in the lab, saying I was probably premature to cast judgment on such a young journal.  And furthermore, some people suggested that I should keep my big mouth shut, as I was a lowly undergrad and, furthermore, this is how things work in academia.

I’m not about to take back what I wrote back then, because I think it was spot on at the time and was a reflection of what the journal’s product was at the time.  But that doesn’t mean that it necessarily holds true today.

PLoS ONE has gained remarkable popularity in such a short time because they avoid one of the major issues that costs many researchers a ton of time and, in many cases, grants: reviewer bias.  I’ve seen it many times in the short time that I’ve been a part of the lab here at WSU, and I’ve come to realize how much of an impact that it has on the ability of a researcher to get a reasonably justified and supported article published (and included with a grant submittal).

In addition, I’ve seen other researchers starting to understand the advantages of publishing in PLoS ONE, and as a result I think the article quality overall has gone up.

Last year I recommended to my lab that they take a look at the journal as a possibility for a future article submission, as it has the tremendous advantages of quick turnaround times for publication (which can be of tangible importance during close grant deadlines) and open access for wider dissemination of your work.

This comes up now as PLoS ONE last week launched a new blog, everyONE, where they’ll be highlighting articles from the journal and trying to stimulate more conversations around their core content.

And I hope they continue to grow, as it provides a nice template for future academic journals to follow their lead with a more interactive approach.

Epigenetics & Chromatin: Epigenetics Goes Open Access


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While Landes Bioscience made headway by debuting a journal devoted solely to epigenetics (Epigenetics), BMC has really opened the door to epigenetics research by debuting the first open-access journal devoted to epigenetics. Epigenetics & Chromatin is a new open-access option for researchers wanting to make their research available to a wider audience. The co-editors, Steven Henikoff and Frank Grosveld, are open to a wide range of topic areas:

Epigenetics & Chromatin will publish articles aimed at understanding how gene and chromosomal elements are regulated and their activities maintained during cell division, self-renewal, differentiation and environmental alteration. Epigenetic research encompasses studies that use model systems to discover and investigate epigenetic mechanisms, as well as studies aimed at combating diseases that involve epigenetic processes. Topics include, but are not limited to, gene activation, silencing and imprinting, cellular reprogramming, nucleosome modification, assembly and remodeling, DNA methylation, chromatin structure and dynamics, chromosomal maintenance elements, dosage compensation, intra- and inter-chromosomal interactions and prion inheritance. Approaches that apply cutting-edge technologies to problems in the field are especially welcome.>

A publication fee of US$1800 is pretty standard fare for an open-access journal, and I’ve heard that many scientists are willing to pay the fee if it means increased awareness (and citations) of their work. I have to believe that with an increased focus on the field from a diverse arrange of disciplines, Epigenetics & Chromatin will be a popular and high impact journal. Link

Hypermethylation of RAS effector related genes and DNA methyltransferase 1 expression in endometrial carcinogenesis.


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Liao X, Siu MK, Chan KY, Wong ES, Ngan HY, Chan QK, Li AS, Khoo US, Cheung AN
Int J Cancer (Jul 2008)

Epigenetic aberration is known to be important in human carcinogenesis. Promoter methylation status of RAS effector related genes, RASSF1A, RASSF2A, hDAB2IP (m2a and m2b regions) and BLU, was evaluated in 76 endometrial carcinomas and their non-neoplastic endometrial tissue by methylation specific PCR. Hypermethylation of at least one of the 5 genes was detected in 73.7% of carcinomas. There were significant correlations between methylation of hDAB2IP and RASSF1A, RASSF2A (p = 0.042, p = 0.012, respectively). Significantly, more frequent RASSF1A hypermethylation was found in Type I endometrioid carcinomas than Type II carcinomas (p = 0.049). Among endometrioid cancers, significant association between RASSF1A hypermethylation and advanced stage, as well as between methylation of hDAB2IP at m2a region with deep myometrial invasion (p < 0.05) was observed. mRNA expression of RASSF1A, RASSF2A and BLU in endometrial cancer cell lines significantly increased after treatment with the demethylating agent 5-Aza-2′-deoxycytidine supporting the repressive effect of hypermethylation on their transcription. Immunohistochemical study of DNMT1 on eight normal endometrium, 16 hyperplastic endometrium without atypia, 40 atypical complex hyperplasia and 79 endometrial carcinomas showed progressive increase in DNMT1 immunoreactivity from normal endometrium to endometrial hyperplasia and endometrioid carcinomas (p = 0.001). Among carcinomas, distinctly higher DNMT1 expression was observed in Type I endometrioid carcinomas (p < 0.001). DNMT1 immunoreactivity correlated with RASSF1A and RASSF2A methylation (p < 0.05). The data suggested that hypermethylation of RAS related genes, particularly RASSF1A, was involved in endometrial carcinogenesis with possible divergent patterns in different histological types. DNMT1 protein overexpression might contribute to such aberrant DNA hypermethylation of specific tumor suppressor genes in endometrial cancers.

The mechanism of myoblast deformation in response to cyclic strain – A cytomechanical study.


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Zheng L, Song J, Li Z, Fan Y, Zhao Z, Chen Y, Deng F, Hu Y
Cell Biol Int (Jul 2008)

Mechanical strain is one of the important epigenetic factors that cause deformation and differentiation of skeletal muscles. This research was designed to investigate how myoblast deformation occurs after cyclic strain loading. Myoblasts were passaged three times and harvested; various cyclic strains (2.5kPa, 5kPa and 10kPa) were then loaded using a pulsatile mechanical system. The adaptive response of the myoblasts was observed at different time points (0.5h, 1h, 6h and 12h) post-loading. At the early stage of cyclic strain loading (<1h), almost no visible morphological changes were observed in the myoblasts. The actin cytoskeleton showed a disordered arrangement and a weak fluorescence expression; there was little expression of talin. At 6h and 12h post-loading, the myoblasts changed their orientation to parallel (in the 2.5kPa and 5kPa groups) or perpendicular (in the 10kPa group) to the direction of strain. Fluorescence expression of both the actin cytoskeleton and talin was significantly increased. The results suggest that cyclic strain has at least two ways to regulate adaptation of myoblasts: (1) by directly affecting actin cytoskeleton at an early stage post-loading to cause depolymerization; and (2) by later chemical signals transmitted from the extracellular side to intracellular side to initiate repolymerization.

Histone lysine methyltransferases and demethylases in Plasmodium falciparum.


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Cui L, Fan Q, Cui L, Miao J
Int J Parasitol (Aug 2008)

Dynamic histone lysine methylation, regulated by methyltransferases and demethylases, plays fundamental roles in chromatin structure and gene expression in a wide range of eukaryotic organisms. A large number of SET-domain-containing proteins make up the histone lysine methyltransferase (HKMT) family, which catalyses the methylation of different lysine residues with relatively high substrate specificities. Another large family of Jumonji C (JmjC)-domain-containing histone lysine demethylases (JHDMs) reverses histone lysine methylation with both lysine site and methyl-state specificities. Through bioinformatic analysis, at least nine SET-domain-containing genes were found in the malaria parasite Plasmodium falciparum and its sibling species. Phylogenetic analysis separated these putative HKMTs into five subfamilies with different putative substrate specificities. Consistent with the phylogenetic subdivision, methyl marks were found on K4, K9 and K36 of histone H3 and K20 of histone H4 by site-specific methyl-lysine antibodies. In addition, most SET-domain genes and histone methyl-lysine marks displayed dynamic changes during the parasite asexual erythrocytic cycle, suggesting that they constitute an important epigenetic mechanism of gene regulation in malaria parasites. Furthermore, the malaria parasite and other apicomplexan genomes also encode JmjC-domain-containing proteins that may serve as histone lysine demethylases. Whereas prokaryotic expression of putative active domains of four P. falciparum SET proteins did not yield detectable HKMT activity towards recombinant P. falciparum histones, two protein domains expressed in vitro in a eukaryotic system showed HKMT activities towards H3 and H4, respectively. With the discovery of these Plasmodium SET- and JmjC-domain genes in the malaria parasite genomes, future efforts will be directed towards elucidation of their substrate specificities and functions in various cellular processes of the parasites.

Individual tumorigenesis pathways of sporadic colorectal adenocarcinomas are associated with the biological behavior of tumors.


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Kim JC, Cho YK, Roh SA, Yu CS, Gong G, Jang SJ, Kim SY, Kim YS
Cancer Sci (Jul 2008)

Clinicopathologic features of sporadic colorectal adenocarcinomas were compared using integrated data from 244 patients subjected to curative resection. Individual steps in the tumorigenesis pathway, that is, adenomatosis polyposis coli (APC), Wnt-activated, base excision repair mutations, mismatch repair defects, RAF-mediated, transforming growth factor (TGF)-beta-suppressed, bone morphogenic protein (BMP)-suppressed, and p53 alterations, were examined in terms of genetic and epigenetic changes, as well as protein expression. Genetic and molecular alterations of right colon cancers were distinct from those of left colon and rectal cancers. Rectal cancers showed the attenuated phenotype of left colon cancers. Tumors most frequently displayed either TGF-beta- or BMP-suppressed alterations (81.2%), followed by RAF-mediated alterations (78.6%), and mismatch repair defects (38.4%), constituting a total of 24 integrated pathways. Tumors lacking APC mutations or carrying the RAF alteration (V600E) were frequently associated with lymphovascular invasion and lymph node metastasis (P < 0.05). Poorly differentiated or mucinous adenocarcinomas were generally associated with high level microsatellite instability, Axin2 suppression, TGF-beta1 or BMPR1A suppression, loss of heterozygosity of D18S46 or D18S474, and absence of base excision repair mutations (P < 0.0001-0.05). Early tumor recurrence was significantly correlated with lack of APC mutations (P = 0.036). Moreover, tumors that concurrently displayed APC/Wnt-activated, TGF-beta/BMP-suppressed, and p53 alterations were significantly predisposed to early recurrence (P = 0.026). Our data clearly indicate that particular steps or pathways of colorectal tumorigenesis are closely associated with characteristic clinicopathologic features that, in turn, determine biological behavior, such as tumor growth, invasion, and recurrence.

Haplotype-specific expression of the human PDGFRA gene correlates with the risk of glioblastomas.


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Toepoel M, Joosten PH, Knobbe CB, Afink GB, Zotz RB, Steegers-Theunissen RP, Reifenberger G, van Zoelen EJ
Int J Cancer (Jul 2008)

Aberrant expression of the platelet-derived growth factor alpha-receptor (PDGFRA) gene has been associated with various diseases, including neural tube defects and gliomas. We have previously identified 5 distinct haplotypes for the PDGFRA promoter region, designated H1, H2alpha, H2beta, H2gamma and H2delta. Of these haplotypes H1 and H2alpha are the most common, whereby H1 drives low and H2alpha high transcriptional activity in transient transfection assays. Here we have investigated the role of these PDGFRA promoter haplotypes in gliomagenesis at both the genetic and cellular level. In a case-control study on 71 glioblastoma patients, we observed a clear underrepresentation of H1 alleles, with pH1 = 0.141 in patients and pH1 = 0.211 in a combined Western European control group (n = 998, p < 0.05). Furthermore, in 3 out of 4 available H1/H2alpha heterozygous human glioblastoma cell lines, H1-derived mRNA levels were more than 10-fold lower than from H2alpha, resulting at least in part from haplotype-specific epigenetic differences such as DNA methylation and histone acetylation. Together, these results indicate that PDGFRA promoter haplotypes may predispose to gliomas. We propose a model in which PDGFRA is upregulated in a haplotype-specific manner during neural stem cell differentiation, which affects the pool size of cells that can later undergo gliomagenesis.

Oxidative stress, DNA methylation and carcinogenesis.


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Franco R, Schoneveld O, Georgakilas AG, Panayiotidis MI
Cancer Lett (Jul 2008)

Transformation of a normal cell to a malignant one requires phenotypic changes often associated with each of the initiation, promotion and progression phases of the carcinogenic process. Genes in each of these phases acquire alterations in their transcriptional activity that are associated either with hypermethylation-induced transcriptional repression (in the case of tumor suppressor genes) or hypomethylation-induced activation (in the case of oncogenes). Growing evidence supports a role of ROS-induced generation of oxidative stress in these epigenetic processes and as such we can hypothesize of potential mode(s) of action by which oxidative stress modulates epigenetic regulation of gene expression. This is of outmost importance given that various components of the epigenetic pathway and primarily aberrant DNA methylation patterns are used as potential biomarkers for cancer diagnosis and prognosis.

Drosophila arginine methyltransferase 1 (DART1) is an ecdysone receptor co-repressor.


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Kimura S, Sawatsubashi S, Ito S, Kouzmenko A, Suzuki E, Zhao Y, Yamagata K, Tanabe M, Ueda T, Fujiyama S, Murata T, Matsukawa H, Takeyama K, Yaegashi N, Kato S
Biochem Biophys Res Commun (Jul 2008)

Histone arginine methylation is an epigenetic marker that regulates gene expression by defining the chromatin state. Arginine methyltransferases, therefore, serve as transcriptional co-regulators. However, unlike other transcriptional co-regulators, the physiological roles of arginine methyltransferases are poorly understood. Drosophila arginine methyltransferase 1 (DART1), the mammalian PRMT1 homologue, methylates the arginine residue of histone H4 (H4R3me2). Disruption of DART1 in Drosophila by imprecise P-element excision resulted in low viability during metamorphosis in the pupal stages. In the pupal stage, an ecdysone hormone signal is critical for developmental progression. DART1 interacted with the nuclear ecdysone receptor (EcR) in a ligand-dependent manner, and co-repressed EcR in intact flies. These findings suggest that DART1, a histone arginine methyltransferase, is a co-repressor of EcR that is indispensable for normal pupal development in the intact fly.

Chromatin organization and virus gene expression.


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Lieberman PM
J Cell Physiol (Aug 2008)

Many viruses introduce DNA into the host-cell nucleus, where they must either embrace or confront chromatin factors as a support or obstacle to completion of their life cycle. Compared to the eukaryotic cell, viruses have compact and rapidly evolving genomes. Despite their smaller size, viruses have complex life cycles that involve dynamic changes in DNA structure. Nuclear entry, transcription, replication, genome stabilization, and virion packaging involve complex changes in chromosome organization and structure. Chromatin dynamics and epigenetic modifications play major roles in viral and host chromosome biology. In some cases, viruses may use novel or viral-specific epigenetic modifying activities, which may reflect variant pathways that distinguish their behavior from the bulk of the cellular chromosome. This review examines several recent discoveries that highlight the role of chromatin dynamics in the life cycle of DNA viruses.

Hepatitis B virus-cell interactions and pathogenesis.


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Nguyen DH, Ludgate L, Hu J
J Cell Physiol (Aug 2008)

Like all viruses, hepatitis B virus (HBV) replication and pathogenesis depends on the critical interplay between viral and host factors. In this review, we will focus on the recent progress in understanding the virus-host interactions at the level of the infected cell. These interactions include the requirement of cellular chaperones for the initiation of HBV reverse transcription, the role of the HBV X protein (HBx) in modifying viral and cellular transcription and signaling, the formation of the HBV episomal DNA and its epigenetic regulation in viral persistence, and the cellular factors involved in viral entry, nucleocapsid maturation, and virion secretion.

Individual tumorigenesis pathways of sporadic colorectal adenocarcinomas are associated with the biological behavior of tumors.


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Kim JC, Cho YK, Roh SA, Yu CS, Gong G, Jang SJ, Kim SY, Kim YS
Cancer Sci (Jul 2008)

Clinicopathologic features of sporadic colorectal adenocarcinomas were compared using integrated data from 244 patients subjected to curative resection. Individual steps in the tumorigenesis pathway, that is, adenomatosis polyposis coli (APC), Wnt-activated, base excision repair mutations, mismatch repair defects, RAF-mediated, transforming growth factor (TGF)-beta-suppressed, bone morphogenic protein (BMP)-suppressed, and p53 alterations, were examined in terms of genetic and epigenetic changes, as well as protein expression. Genetic and molecular alterations of right colon cancers were distinct from those of left colon and rectal cancers. Rectal cancers showed the attenuated phenotype of left colon cancers. Tumors most frequently displayed either TGF-beta- or BMP-suppressed alterations (81.2%), followed by RAF-mediated alterations (78.6%), and mismatch repair defects (38.4%), constituting a total of 24 integrated pathways. Tumors lacking APC mutations or carrying the RAF alteration (V600E) were frequently associated with lymphovascular invasion and lymph node metastasis (P < 0.05). Poorly differentiated or mucinous adenocarcinomas were generally associated with high level microsatellite instability, Axin2 suppression, TGF-beta1 or BMPR1A suppression, loss of heterozygosity of D18S46 or D18S474, and absence of base excision repair mutations (P < 0.0001-0.05). Early tumor recurrence was significantly correlated with lack of APC mutations (P = 0.036). Moreover, tumors that concurrently displayed APC/Wnt-activated, TGF-beta/BMP-suppressed, and p53 alterations were significantly predisposed to early recurrence (P = 0.026). Our data clearly indicate that particular steps or pathways of colorectal tumorigenesis are closely associated with characteristic clinicopathologic features that, in turn, determine biological behavior, such as tumor growth, invasion, and recurrence.

Frequent silencing of a putative tumor suppressor gene melatonin receptor 1 A (MTNR1A) in oral squamous-cell carcinoma.


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Nakamura E, Kozaki K, Tsuda H, Suzuki E, Pimkhaokham A, Yamamoto G, Irie T, Tachikawa T, Amagasa T, Inazawa J, Imoto I
Cancer Sci (Jul 2008)

Array-based comparative genomic hybridization (array-CGH) has good potential for the high-throughput identification of genetic aberrations in cell genomes. In the course of a program to screen a panel of 21 oral squamous-cell carcinoma (OSCC) cell lines for genome-wide copy-number aberrations by array-CGH using our in-house bacterial artificial chromosome arrays, we identified a frequent homozygous deletion at 4q35 loci with approximately 1 Mb in extent. Among the seven genes located within this region, the expression of the melatonin receptor 1 A (MTNR1A) messenger RNA (mRNA) was not detected or decreased in 35 out of the 39 (89%) OSCC cell lines, but was detected in immortalized normal oral epithelial cell line, and was restored in gene-silenced OSCC cells without its homozygous loss after treatment with 5-aza-2′-deoxycytidine. The hypermethylation of the CpG (cytosine and guanine separated by phosphate) island in the promoter region of MTNR1A was inversely correlated with its expression in OSCC lines without a homozygous deletion. Methylation of this CpG island was also observed in primary OSCC tissues. In an immunohistochemical analysis of 50 primary OSCC tumors, the absence of immunoreactive MTNR1A was significantly associated with tumor size and a shorter overall survival in patients with OSCC tumors, and seems to be an independent prognosticator in a multivariate analysis. Exogenous restoration of MTNR1A expression inhibited the growth of OSCC cells lacking its expression. Together with the known tumor-suppressive function of melatonin and MTNR1A in various tumors, our results indicate MTNR1A to be the most likely target for epigenetic silencing at 4q35 and to play a pivotal role during oral carcinogenesis.

X-inactivation reveals epigenetic anomalies in most hESC but identifies sublines that initiate as expected.


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Hall LL, Byron M, Butler J, Becker KA, Nelson A, Amit M, Itskovitz-Eldor J, Stein J, Stein G, Ware C, Lawrence JB
J Cell Physiol (Aug 2008)

The clinical and research value of human embryonic stem cells (hESC) depends upon maintaining their epigenetically nave, fully undifferentiated state. Inactivation of one X chromosome in each cell of mammalian female embryos is a paradigm for one of the earliest steps in cell specialization through formation of facultative heterochromatin. Mouse ES cells are derived from the inner cell mass (ICM) of blastocyst stage embryos prior to X-inactivation, and cultured murine ES cells initiate this process only upon differentiation. Less is known about human X-inactivation during early development. To identify a human ES cell model for X-inactivation and study differences in the epigenetic state of hESC lines, we investigated X-inactivation in all growth competent, karyotypically normal, NIH approved, female hESC lines and several sublines. In the vast majority of undifferentiated cultures of nine lines examined, essentially all cells exhibit hallmarks of X-inactivation. However, subcultures of any hESC line can vary in X-inactivation status, comprising distinct sublines. Importantly, we identified rare sublines that have not yet inactivated Xi and retain competence to undergo X-inactivation upon differentiation. Other sublines exhibit defects in counting or maintenance of XIST expression on Xi. The few hESC sublines identified that have not yet inactivated Xi may reflect the earlier epigenetic state of the human ICM and represent the most promising source of NIH hESC for study of human X-inactivation. The many epigenetic anomalies seen indicate that maintenance of fully unspecialized cells, which have not formed Xi facultative heterochromatin, is a delicate epigenetic balance difficult to maintain in culture.

Oogenesis: Prospects and challenges for the future.


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Rodrigues P, Limback D, McGinnis LK, Plancha CE, Albertini DF
J Cell Physiol (Aug 2008)

Oogenesis serves a singular role in the reproductive success of plants and animals. Of their remarkable differentiation pathway what stands out is the ability of oocytes to transform from a single cell into the totipotent lineages that seed the early embryo. As our understanding that commonalities between diverse organisms at the genetic, cellular and molecular levels are conserved to achieve successful reproduction, the notion that embryogenesis presupposes oogenesis has entered the day-to-day parlance of regenerative medicine and stem cell biology. With emphasis on the mammalian oocyte, this review will cover (1) current concepts regarding the birth, survival and growth of oocytes that depends on complex patterns of cell communication between germ line and soma, (2) the notion of “maternal inheritance” from a genetic and epigenetic perspective, and (3) the relative value of model systems with reference to current clinical and biotechnology applications.