Aberrant DNA Methylation Reprogramming During Induced Pluripotent Stem Cell Generation is Dependent on the Choice of Reprogramming Factors

The conversion of somatic cells into pluripotent stem cells via overexpression of reprogramming factors involves epigenetic remodeling. DNA methylation at a significant proportion of CpG sites in induced pluripotent stem cells (iPSCs) differs from that of embryonic stem cells (ESCs). Whether different sets of reprogramming factors influence the type and extent of aberrant DNA methylation in iPSCs differently remains unknown. In order to help resolve this critical question, we generated human iPSCs from a common fibroblast cell source using either the Yamanaka factors (OCT4, SOX2, KLF4 and cMYC) or the Thomson factors (OCT4, SOX2, NANOG and LIN28), and determined their genome-wide DNA methylation profiles. In addition to shared DNA methylation aberrations present in all our iPSCs, we identified Yamanaka-iPSC (Y-iPSC)-specific and Thomson-iPSC (T-iPSC)-specific recurrent aberrations. Strikingly, not only were the genomic locations of the aberrations different but also their types: reprogramming with Yamanaka factors mainly resulted in failure to demethylate CpGs, whereas reprogramming with Thomson factors mainly resulted in failure to methylate CpGs. Differences in the level of transcripts encoding DNMT3b and TET3 between Y-iPSCs and T-iPSCs may contribute partially to the distinct types of aberrations. Finally, de novo aberrantly methylated genes in Y-iPSCs were enriched for NANOG targets that are also aberrantly methylated in some cancers. Our study thus reveals that the choice of reprogramming factors influences the amount, location, and class of DNA methylation aberrations in iPSCs. These findings may provide clues into how to produce human iPSCs with fewer DNA methylation abnormalities

Volatile and Organic Compositions of Sedimentary Rocks in Yellowknife Bay, Gale crater, Mars

H₂O, CO₂, SO₂, O₂, H₂, H₂S, HCl, chlorinated hydrocarbons, NO and other trace gases were evolved during pyrolysis of two mudstone samples acquired by the Curiosity rover at Yellowknife Bay within Gale crater, Mars. H₂O/OH-bearing phases included 2:1 phyllosilicate(s), bassanite, akaganeite, and amorphous materials. Thermal decomposition of carbonates and combustion of organic materials are candidate sources for the CO₂. Concurrent evolution of O₂ and chlorinated hydrocarbons suggest the presence of oxychlorine phase(s). Sulfides are likely sources for S-bearing species. Higher abundances of chlorinated hydrocarbons in the mudstone compared with Rocknest windblown materials previously analyzed by Curiosity suggest that indigenous martian or meteoritic organic C sources may be preserved in the mudstone; however, the C source for the chlorinated hydrocarbons is not definitively of martian origin

The Petrochemistry of Jake_M: A Martian Mugearite

“Jake_M,” the first rock analyzed by the Alpha Particle X-ray Spectrometer instrument on the Curiosity rover, differs substantially in chemical composition from other known martian igneous rocks: It is alkaline (>15% normative nepheline) and relatively fractionated. Jake_M is compositionally similar to terrestrial mugearites, a rock type typically found at ocean islands and continental rifts. By analogy with these comparable terrestrial rocks, Jake_M could have been produced by extensive fractional crystallization of a primary alkaline or transitional magma at elevated pressure, with or without elevated water contents. The discovery of Jake_M suggests that alkaline magmas may be more abundant on Mars than on Earth and that Curiosity could encounter even more fractionated alkaline rocks (for example, phonolites and trachytes)

Elemental Geochemistry of Sedimentary Rocks at Yellowknife Bay, Gale Crater, Mars

Sedimentary rocks examined by the Curiosity rover at Yellowknife Bay, Mars, were derived from sources that evolved from approximately average Martian crustal composition to one influenced by alkaline basalts. No evidence of chemical weathering is preserved indicating arid, possibly cold, paleoclimates and rapid erosion/deposition. Absence of predicted geochemical variations indicates that magnetite and phyllosilicates formed by diagenesis under low temperature, circum-neutral pH, rock-dominated aqueous conditions. High spatial resolution analyses of diagenetic features, including concretions, raised ridges and fractures, indicate they are composed of iron- and halogen-rich components, magnesium-iron-chlorine-rich components and hydrated calcium-sulfates, respectively. Composition of a cross-cutting dike-like feature is consistent with sedimentary intrusion. Geochemistry of these sedimentary rocks provides further evidence for diverse depositional and diagenetic sedimentary environments during the early history of Mars

A Habitable Fluvio-Lacustrine Environment at Yellowknife Bay, Gale Crater, Mars

The Curiosity rover discovered fine-grained sedimentary rocks, inferred to represent an ancient lake, preserve evidence of an environment that would have been suited to support a Martian biosphere founded on chemolithoautotrophy. This aqueous environment was characterized by neutral pH, low salinity, and variable redox states of both iron and sulfur species. C, H, O, S, N, and P were measured directly as key biogenic elements, and by inference N and P are assumed to have been available. The environment likely had a minimum duration of hundreds to tens of thousands of years. These results highlight the biological viability of fluvial-lacustrine environments in the post-Noachian history of Mars

X-ray Diffraction Results from Mars Science Laboratory: Mineralogy of Rocknest at Gale Crater

The Mars Science Laboratory rover Curiosity scooped samples of soil from the Rocknest aeolian bedform in Gale crater. Analysis of the soil with the Chemistry and Mineralogy (CheMin) x-ray diffraction (XRD) instrument revealed plagioclase (~An57), forsteritic olivine (~Fo62), augite, and pigeonite, with minor K-feldspar, magnetite, quartz, anhydrite, hematite, and ilmenite. The minor phases are present at, or near, detection limits. The soil also contains 27 ± 14 weight percent x-ray amorphous material, likely containing multiple Fe^(3+)- and volatile-bearing phases, including possibly a substance resembling hisingerite. The crystalline component is similar to the normative mineralogy of certain basaltic rocks from Gusev crater on Mars and of martian basaltic meteorites. The amorphous component is similar to that found on Earth in places such as soils on the Mauna Kea volcano, Hawaii

Mineralogy of a Mudstone at Yellowknife Bay, Gale Crater, Mars

Sedimentary rocks at Yellowknife Bay (Gale Crater) on Mars include mudstone sampled by the Curiosity rover. The samples, John Klein and Cumberland, contain detrital basaltic minerals, Ca-sulfates, Fe oxide/hydroxides, Fe-sulfides, amorphous material, and trioctahedral smectites. The John Klein smectite has basal spacing of ~10 Å indicating little interlayer hydration. The Cumberland smectite has basal spacing at ~13.2 Å as well as ~10 Å. The ~13.2 Å spacing suggests a partially chloritized interlayer or interlayer Mg or Ca facilitating H_2O retention. Basaltic minerals in the mudstone are similar to those in nearby eolian deposits. However, the mudstone has far less Fe-forsterite, possibly lost with formation of smectite plus magnetite. Late Noachian/Early Hesperian or younger age indicates that clay mineral formation on Mars extended beyond Noachian time

Pre-neoplastic Epigenetic Disruption Enhancers In Chronic Inflammation Of Transcriptional

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Chronic periodontitis (CP) is a chronic inflammatory disease independently associated with higher incidence of oral cavity squamous cell carcinoma (OSCC). However, the molecular mechanism responsible for this increased incidence is unknown. Here we profiled the DNA methylome of CP patients and healthy controls and compared to a large set of OSCC samples from TCGA. We observed a significant overlap between the altered DNA methylation patterns in CP and in OSCC, suggesting an emergence of a pre-neoplastic epigenome in CP. Remarkably, the hypermethylated CpGs in CP were significantly enriched for enhancer elements. This aberrant enhancer methylation is functional and able to disrupt enhancer activity by preventing the binding of chromatin looping factors. This study provides new insights on the molecular mechanisms linking chronic inflammation and tumor predisposition, highlighting the role of epigenetic disruption of transcriptional enhancers.71577215786Cancer Research Society [CRS19092, CRS19091]Canadian Cancer Society [CCSRI703279, CCSRI703716]NSERC [489073]Ontario Institute for Cancer Research (OTCR)province of OntarioPrincess Margaret Cancer FoundationUniversity of Toronto McLaughlin Centre [MC-2015-02]FAPESP [2010/08180-0, 2010/05151-9, 2014/05867-5, 2014/20167-0]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Association of matrix metalloproteinase gene polymorphism with temporomandibular joint degeneration

Temporomandibular joint (TMJ) degeneration is a frequent cause of orofacial pain. Matrix metalloproteinases (MMPs) degrade extracellular matrix components and play an important role in TMJ degeneration. We investigated the frequency of the MMP1 1G/2G polymorphism (rs1799750), the MMP3 5A/6A polymorphism (rs3025058), and the MMP9 C/T polymorphism (rs3918242) in individuals with TMJ degeneration, in order to analyze the association of polymorphisms in these genes with TMJ degeneration. The population studied comprised 117 healthy controls and 115 individuals diagnosed with TMJ degeneration upon examination of magnetic resonance imaging (MRI) and computed tomography (CT) images. Genotypes were determined using PCR restriction fragment length polymorphism (RFLP). Logistic regression analyses revealed an association between the MMP1 2G/2G genotype and degeneration; in contrast, there was no association between either the MMP3 or the MMP9 genotype and degeneration. Our results may indicate a role for the MMP1 polymorphism in TMJ degeneration.11911