Deep sequencing of HPV E6/E7 genes reveals loss of genotypic diversity and gain of clonal dominance in high-grade intraepithelial lesions of the cervix

Table S2. HPV E6/E7 sequencing: dideoxy (Sanger) vs. deep (Illumina). (PDF 236 kb

Heritable clustering and pathway discovery in breast cancer integrating epigenetic and phenotypic data

BACKGROUND: In order to recapitulate tumor progression pathways using epigenetic data, we developed novel clustering and pathway reconstruction algorithms, collectively referred to as heritable clustering. This approach generates a progression model of altered DNA methylation from tumor tissues diagnosed at different developmental stages. The samples act as surrogates for natural progression in breast cancer and allow the algorithm to uncover distinct epigenotypes that describe the molecular events underlying this process. Furthermore, our likelihood-based clustering algorithm has great flexibility, allowing for incomplete epigenotype or clinical phenotype data and also permitting dependencies among variables. RESULTS: Using this heritable clustering approach, we analyzed methylation data obtained from 86 primary breast cancers to recapitulate pathways of breast tumor progression. Detailed annotation and interpretation are provided to the optimal pathway recapitulated. The result confirms the previous observation that aggressive tumors tend to exhibit higher levels of promoter hypermethylation. CONCLUSION: Our results indicate that the proposed heritable clustering algorithms are a useful tool for stratifying both methylation and clinical variables of breast cancer. The application to the breast tumor data illustrates that this approach can select meaningful progression models which may aid the interpretation of pathways having biological and clinical significance. Furthermore, the framework allows for other types of biological data, such as microarray gene expression or array CGH data, to be integrated

Fluid generation and evolution during exhumation of deeply subducted UHP continental crust: Petrogenesis of composite granite-quartz veins in the Sulu belt, China

Composite granite-quartz veins occur in retrogressed ultrahigh pressure (UHP) eclogite enclosed in gneiss at General's Hill in the central Sulu belt, eastern China. The granite in the veins has a high-pressure (HP) mineral assemblage of dominantly quartz+phengite+allanite/epidote+garnet that yields pressures of 2.5-2.1 GPa (Si-in-phengite barometry) and temperatures of 850-780°C (Ti-in-zircon thermometry) at 2.5 GPa (~20°C lower at 2.1 GPa). Zircon overgrowths on inherited cores and new grains of zircon from both components of the composite veins crystallized at c. 221 Ma. This age overlaps the timing of HP retrograde recrystallization dated at 225-215 Ma from multiple localities in the Sulu belt, consistent with the HP conditions retrieved from the granite. The eHf(t) values of new zircon from both components of the composite veins and the Sr-Nd isotope compositions of the granite consistently lie between values for gneiss and eclogite, whereas d18O values of new zircon are similar in the veins and the crustal rocks. These data are consistent with zircon growth from a blended fluid generated internally within the gneiss and the eclogite, without any ingress of fluid from an external source. However, at the peak metamorphic pressure, which could have reached 7 GPa, the rocks were likely fluid absent. During initial exhumation under UHP conditions, exsolution of H2O from nominally anhydrous minerals generated a grain boundary supercritical fluid in both gneiss and eclogite. As exhumation progressed, the volume of fluid increased allowing it to migrate by diffusing porous flow from grain boundaries into channels and drain from the dominant gneiss through the subordinate eclogite. This produced a blended fluid intermediate in its isotope composition between the two end-members, as recorded by the composite veins. During exhumation from UHP (coesite) eclogite to HP (quartz) eclogite facies conditions, the supercritical fluid evolved by dissolution of the silicate mineral matrix, becoming increasingly solute-rich, more 'granitic' and more viscous until it became trapped. As crystallization began by diffusive loss of H2O to the host eclogite concomitant with ongoing exhumation of the crust, the trapped supercritical fluid intersected the solvus for the granite-H2O system, allowing phase separation and formation of the composite granite-quartz veins. Subsequently, during the transition from HP eclogite to amphibolite facies conditions, minor phengite breakdown melting is recorded in both the granite and the gneiss by K-feldspar+plagioclase+biotite aggregates located around phengite and by K-feldspar veinlets along grain boundaries. Phase equilibria modelling of the granite indicates that this late-stage melting records P-T conditions towards the end of the exhumation, with the subsolidus assemblage yielding 0.7-1.1 GPa at <670°C. Thus, the composite granite-quartz veins represent a rare example of a natural system recording how the fluid phase evolved during exhumation of continental crust. The successive availability of different fluid phases attending retrograde metamorphism from UHP eclogite to amphibolite facies conditions will affect the transport of trace elements through the continental crust and the role of these fluids as metasomatic agents interacting with the mantle wedge in the subduction channel

Inference of hierarchical regulatory network of estrogen-dependent breast cancer through ChIP-based data

<p>Abstract</p> <p>Background</p> <p>Global profiling of in vivo protein-DNA interactions using ChIP-based technologies has evolved rapidly in recent years. Although many genome-wide studies have identified thousands of ERα binding sites and have revealed the associated transcription factor (TF) partners, such as AP1, FOXA1 and CEBP, little is known about ERα associated hierarchical transcriptional regulatory networks.</p> <p>Results</p> <p>In this study, we applied computational approaches to analyze three public available ChIP-based datasets: ChIP-seq, ChIP-PET and ChIP-chip, and to investigate the hierarchical regulatory network for ERα and ERα partner TFs regulation in estrogen-dependent breast cancer MCF7 cells. 16 common TFs and two common new TF partners (RORA and PITX2) were found among ChIP-seq, ChIP-chip and ChIP-PET datasets. The regulatory networks were constructed by scanning the ChIP-peak region with TF specific position weight matrix (PWM). A permutation test was performed to test the reliability of each connection of the network. We then used DREM software to perform gene ontology function analysis on the common genes. We found that FOS, PITX2, RORA and FOXA1 were involved in the up-regulated genes.</p> <p>We also conducted the ERα and Pol-II ChIP-seq experiments in tamoxifen resistance MCF7 cells (denoted as MCF7-T in this study) and compared the difference between MCF7 and MCF7-T cells. The result showed very little overlap between these two cells in terms of targeted genes (21.2% of common genes) and targeted TFs (25% of common TFs). The significant dissimilarity may indicate totally different transcriptional regulatory mechanisms between these two cancer cells.</p> <p>Conclusions</p> <p>Our study uncovers new estrogen-mediated regulatory networks by mining three ChIP-based data in MCF7 cells and ChIP-seq data in MCF7-T cells. We compared the different ChIP-based technologies as well as different breast cancer cells. Our computational analytical approach may guide biologists to further study the underlying mechanisms in breast cancer cells or other human diseases.</p

RCS2 J232727.6-020437: An Efficient Cosmic Telescope at z=0.6986z=0.6986

We present a detailed gravitational lens model of the galaxy cluster RCS2 J232727.6-020437. Due to cosmological dimming of cluster members and ICL, its high redshift ($z=0.6986$) makes it ideal for studying background galaxies. Using new ACS and WFC3/IR HST data, we identify 16 multiple images. From MOSFIRE follow up, we identify a strong emission line in the spectrum of one multiple image, likely confirming the redshift of that system to $z=2.083$. With a highly magnified ($\mu\gtrsim2$) source plane area of $\sim0.7$ arcmin$^2$ at $z=7$, RCS2 J232727.6-020437 has a lensing efficiency comparable to the Hubble Frontier Fields clusters. We discover four highly magnified $z\sim7$ candidate Lyman-break galaxies behind the cluster, one of which may be multiply-imaged. Correcting for magnification, we find that all four galaxies are fainter than $0.5 L_{\star}$. One candidate is detected at ${>10\sigma}$ in both Spitzer/IRAC [3.6] and [4.5] channels. A spectroscopic follow-up with MOSFIRE does not result in the detection of the Lyman-alpha emission line from any of the four candidates. From the MOSFIRE spectra we place median upper limits on the Lyman-alpha flux of $5-14 \times 10^{-19}\, \mathrm{erg \,\, s^{-1} cm^{-2}}$ ($5\sigma$).Comment: 14 pages, 9 figures, submitted to ApJ on 3/06/201

Diverse histone modifications on histone 3 lysine 9 and their relation to DNA methylation in specifying gene silencing

<p>Abstract</p> <p>Background</p> <p>Previous studies of individual genes have shown that in a self-enforcing way, dimethylation at histone 3 lysine 9 (dimethyl-H3K9) and DNA methylation cooperate to maintain a repressive mode of inactive genes. Less clear is whether this cooperation is generalized in mammalian genomes, such as mouse genome. Here we use epigenomic tools to simultaneously interrogate chromatin modifications and DNA methylation in a mouse leukemia cell line, L1210.</p> <p>Results</p> <p>Histone modifications on H3K9 and DNA methylation in L1210 were profiled by both global CpG island array and custom mouse promoter array analysis. We used chromatin immunoprecipitation microarray (ChIP-chip) to examine acetyl-H3K9 and dimethyl-H3K9. We found that the relative level of acetyl-H3K9 at different chromatin positions has a wider range of distribution than that of dimethyl-H3K9. We then used differential methylation hybridization (DMH) and the restriction landmark genome scanning (RLGS) to analyze the DNA methylation status of the same targets investigated by ChIP-chip. The results of epigenomic profiling, which have been independently confirmed for individual loci, show an inverse relationship between DNA methylation and histone acetylation in regulating gene silencing. In contrast to the previous notion, dimethyl-H3K9 seems to be less distinct in specifying silencing for the genes tested.</p> <p>Conclusion</p> <p>This study demonstrates in L1210 leukemia cells a diverse relationship between histone modifications and DNA methylation in the maintenance of gene silencing. Acetyl-H3K9 shows an inverse relationship between DNA methylation and histone acetylation in regulating gene silencing as expected. However, dimethyl-H3K9 seems to be less distinct in relation to promoter methylation. Meanwhile, a combination of epigenomic tools is of help in understanding the heterogeneity of epigenetic regulation, which may further our vision accumulated from single-gene studies.</p

Spitzer UltRa Faint SUrvey Program (SURFS UP). II. IRAC-Detected Lyman-Break Galaxies at 6 < z < 10 Behind Strong-Lensing Clusters

We study the stellar population properties of the IRAC-detected $6 \lesssim z \lesssim 10$ galaxy candidates from the Spitzer UltRa Faint SUrvey Program (SURFS UP). Using the Lyman Break selection technique, we find a total of 16 new galaxy candidates at $6 \lesssim z \lesssim 10$ with $S/N \geq 3$ in at least one of the IRAC $3.6\mu$m and $4.5\mu$m bands. According to the best mass models available for the surveyed galaxy clusters, these IRAC-detected galaxy candidates are magnified by factors of $\sim 1.2$--$5.5$. We find that the IRAC-detected $6 \lesssim z \lesssim 10$ sample is likely not a homogeneous galaxy population: some are relatively massive (stellar mass as high as $4 \times 10^9\,M_{\odot}$) and evolved (age $\lesssim 500$ Myr) galaxies, while others are less massive ($M_{\text{stellar}}\sim 10^8\,M_{\odot}$) and very young ($\sim 10$ Myr) galaxies with strong nebular emission lines that boost their rest-frame optical fluxes. We identify two Ly$\alpha$ emitters in our sample from the Keck DEIMOS spectra, one at $z_{\text{Ly}\alpha}=6.76$ (in RXJ1347) and one at $z_{\text{Ly}\alpha}=6.32$ (in MACS0454). We show that IRAC $[3.6]-[4.5]$ color, when combined with photometric redshift, can be used to identify galaxies likely with strong nebular emission lines within certain redshift windows.Comment: ApJ in pres