Time course metabolome of Roux-en-Y gastric bypass confirms correlation between leptin, body weight and the microbiome

Roux-en-Y gastric bypass (RYGB) is an effective way to lose weight and reverse type 2 dia- betes. We profiled the metabolome of 18 obese patients (nine euglycemic and nine diabet- ics) that underwent RYGB surgery and seven lean subjects. Plasma samples from the obese patients were collected before the surgery and one week and three months after the surgery. We analyzed the metabolome in association to five hormones (Adiponectin, Insulin, Ghrelin, Leptin, and Resistin), four peptide hormones (GIP, Glucagon, GLP1, and PYY), and two cytokines (IL-6 and TNF). PCA showed samples cluster by surgery time and many microbially driven metabolites (indoles in particular) correlated with the three months after the surgery. Network analysis of metabolites revealed a connection between carbohydrate (mannosamine and glucosamine) and glyoxylate and confirms glyoxylate association to dia- betes. Only leptin and IL-6 had a significant association with the measured metabolites. Lep- tin decreased immediately after RYGB (before significant weight loss), whereas IL-6 showed no consistent response to RYGB. Moreover, leptin associated with tryptophan in support of the possible role of leptin in the regulation of serotonin synthesis pathways in the gut. These results suggest a potential link between gastric leptin and microbial-derived metabolites in the context of obesity and diabetes

Nuclear AGO1 Regulates Gene Expression by Affecting Chromatin Architecture in Human Cells

The impact of mammalian RNA interference components, particularly, Argonaute proteins, on chromatin organization is unexplored. Recent reports indicate that AGO1 association with chromatin appears to influence gene expression. To uncover the role of AGO1 in the nucleus, we used a combination of genome-wide approaches in control and AGO1-depleted HepG2 cells. We found that AGO1 strongly associates with active enhancers and RNA being produced at those sites. Hi-C analysis revealed AGO1 enrichment at the boundaries of topologically associated domains (TADs). By Hi-C in AGO1 knockdown cells, we observed changes in chromatin organization, including TADs and A/B compartment mixing, specifically in AGO1-bound regions. Distinct groups of genes and especially eRNA transcripts located within differentially interacting loci showed altered expression upon AGO1 depletion. Moreover, AGO1 association with enhancers is dependent on eRNA transcription. Collectively, our data suggest that enhancer-associated AGO1 contributes to the fine-tuning of chromatin architecture and gene expression in human cells

Hologenome analysis of two marine sponges with different microbiomes

Background: Sponges (Porifera) harbor distinct microbial consortia within their mesohyl interior. We herein analysed the hologenomes of Stylissa carteri and Xestospongia testudinaria, which notably differ in their microbiome content. Results: Our analysis revealed that S. carteri has an expanded repertoire of immunological domains, specifically Scavenger Receptor Cysteine-Rich (SRCR) like domains, compared to X. testudinaria. On the microbial side, metatranscriptome analyses revealed an overrepresentation of potential symbiosis-related domains in X. testudinaria. Conclusions: Our findings provide genomic insights into the molecular mechanisms underlying host-symbiont coevolution and may serve as a roadmap for future hologenome analyses

The evolution of ultraconserved elements with different phylogenetic origins

<p>Abstract</p> <p>Background</p> <p>Ultraconserved elements of DNA have been identified in vertebrate and invertebrate genomes. These elements have been found to have diverse functions, including enhancer activities in developmental processes. The evolutionary origins and functional roles of these elements in cellular systems, however, have not yet been determined.</p> <p>Results</p> <p>Here, we identified a wide range of ultraconserved elements common to distant species, from primitive aquatic organisms to terrestrial species with complicated body systems, including some novel elements conserved in fruit fly and human. In addition to a well-known association with developmental genes, these DNA elements have a strong association with genes implicated in essential cell functions, such as epigenetic regulation, apoptosis, detoxification, innate immunity, and sensory reception. Interestingly, we observed that ultraconserved elements clustered by sequence similarity. Furthermore, species composition and flanking genes of clusters showed lineage-specific patterns. Ultraconserved elements are highly enriched with binding sites to developmental transcription factors regardless of how they cluster.</p> <p>Conclusion</p> <p>We identified large numbers of ultraconserved elements across distant species. Specific classes of these conserved elements seem to have been generated before the divergence of taxa and fixed during the process of evolution. Our findings indicate that these ultraconserved elements are not the exclusive property of higher modern eukaryotes, but rather transmitted from their metazoan ancestors.</p

Nucleosome landscape at HCNEs.

<p>(A) Mean nucleosome density of sequences aligned with respect to their centers. Nucleosomes are enriched at the centers of HCNEs compared to the flanking regions. (B) Mononucleosome enrichment was calculated from sequences aligned as described in (A). Mononucleosomes are depleted in HCNEs compared to flanking regions. (C) H3.3 enrichment, calculated from sequences aligned as described in (A). H3.3 is depleted at HCNEs compared to the flanking regions. (D) Same as (C) but for H3.3dN.</p

Genomic properties of HCNEs.

<p>(A) Violin plot illustrating that HCNEs have a higher GC content versus 10,000 random non-coding sequences. (B) Per-base A+T frequencies within 200 bp of HCNE-flanking regions and 15 bp of HCNEs aligned at their boundaries (region on downstream boundaries were reversed). (C) Sequence logos of four TFBSs that were among the most significant matches to overrepresented heptamers; red marks TFs reported to be involved in developmental processes; for complete list of TFBSs matches to top 50 overrepresented heptamers refer to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109326#pone.0109326.s005" target="_blank">Table S2</a>. (D) Bar plot showing the fraction of core promoter predictions among the HCNE-proximal genes. HCNE-proximal genes are enriched in the Inr-motif and depleted of Motif1/6 and DRE core promoters, to a higher degree than expected by chance. (E) GO enrichment among HCNE-proximal genes grouped by their core promoter type. The top 10 significantly enriched terms (Holm-Bonferroni adjusted P-values <0.05) are shown for each promoter-type group. Colors represent –log₁₀ (Holm-Bonferroni adjusted P-values).</p

Genomic and epigenomic properties of HCNEs.

<p>(A) Heatmap demonstrating the clustering of HCNEs based on the studied features (see below). (B) Heatmap showing correlation between features. The studied features include: the levels of nucleosomes, mononucleosomes, H3.3 and H3.3dN; the summed occurrence of each histone modification and the CBP binding for each HCNE during development; the replication timing in the three studied cell lines (columns labeled as RepTimeBg3, RepTimeS2 and RepTimeKc); and the LAD scores. To facilitate visualization, the values of each feature were scaled to between 0 and 1 using the equation(<i>value – min)/(max – min)</i>, where <i>max</i> and <i>min</i> were the maximum and minimum values of each feature, respectively; complete linkage hierarchical clustering is performed with Euclidean distance as the distance metric.</p

Dynamic Epigenetic Control of Highly Conserved Noncoding Elements

<div><p>Background</p><p>Many noncoding genomic loci have remained constant over long evolutionary periods, suggesting that they are exposed to strong selective pressures. The molecular functions of these elements have been partially elucidated, but the fundamental reason for their extreme conservation is still unknown.</p><p>Results</p><p>To gain new insights into the extreme selection of highly conserved noncoding elements (HCNEs), we used a systematic analysis of multi-omic data to study the epigenetic regulation of such elements during the development of <i>Drosophila melanogaster</i>. At the sequence level, HCNEs are GC-rich and have a characteristic oligomeric composition. They have higher levels of stable nucleosome occupancy than their flanking regions, and lower levels of mononucleosomes and H3.3, suggesting that these regions reside in compact chromatin. Furthermore, these regions showed remarkable modulations in histone modification and the expression levels of adjacent genes during development. Although HCNEs are primarily initiated late in replication, about 10% were related to early replication origins. Finally, HCNEs showed strong enrichment within lamina-associated domains.</p><p>Conclusion</p><p>HCNEs have distinct and protective sequence properties, undergo dynamic epigenetic regulation, and appear to be associated with the structural components of the chromatin, replication origins, and nuclear matrix. These observations indicate that such elements are likely to have essential cellular functions, and offer insights into their epigenetic properties.</p></div

Dynamic histone modification at HCNEs during <i>Drosophila</i> development.

<p>Table shows the percentage of HCNEs that were positive for any of the six analyzed histone modification markers or CBP binding across 12 developmental stages. A dash (−) indicates missing data. An HCNE is considered to have a given marker when at least 10% of its length overlapped with the marker. We observed a prominent presence of H3K27me3 and H3K9me3 among the HCNEs throughout development. Markers associated with the active chromatin state (H3K27ac, H3K9ac, and H3K4me3) displayed stage-specific patterns.</p><p>Dynamic histone modification at HCNEs during <i>Drosophila</i> development.</p