An Integrated Platform for Genome-wide Mapping of Chromatin States Using High-throughput ChIP-sequencing in Tumor Tissues

Histone modifications constitute a major component of the epigenome and play important regulatory roles in determining the transcriptional status of ...

Divergence of Root Microbiota in Different Habitats based on Weighted Correlation Networks

The root microbiome plays an important role in plant growth and environmental adaptation. Network analysis is an important tool for studying communities, ...

University of Texas MD Anderson Cancer Center

Guizhou Normal University

Immune checkpoint therapies exhibit impressive efficacy in some patients with melanoma or lung cancer, but the lack of response in most cases presses the question of how general efficacy can be improved. In addressing this question, we generated a preclinical tumor model to study anti-PD-1 resistance by in vivo passaging of Kras-mutated, p53-deficient murine lung cancer cells (p53(R172HΔg/+)K-ras(LA1/+) ) in a syngeneic host exposed to repetitive dosing with anti-mouse PD-1 antibodies. PD-L1 (CD274) expression did not differ between the resistant and parental tumor cells. However, the expression of important molecules in the antigen presentation pathway, including MHC class I and II, as well as β2-microglobulin, were significantly downregulated in the anti-PD-1-resistant tumors compared with parental tumors. Resistant tumors also contained fewer CD8(+) (CD8α) and CD4(+) tumor-infiltrating lymphocytes and reduced production of IFNγ. Localized radiotherapy induced IFNβ production, thereby elevating MHC class I expression on both parental and resistant tumor cells and restoring the responsiveness of resistant tumors to anti-PD-1 therapy. Conversely, blockade of type I IFN signaling abolished the effect of radiosensitization in this setting. Collectively, these results identify a mechanism of PD-1 resistance and demonstrate that adjuvant radiotherapy can overcome resistance. These findings have immediate clinical implications for extending the efficacy of anti-PD-1 immune checkpoint therapy in patients. Cancer Res; 77(4); 839-50. ©2016 AACR.

Suppression of Type I IFN Signaling in Tumors Mediates Resistance to Anti-PD-1 Treatment That Can Be Overcome by Radiotherapy.

Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. Telomeres were shorter in tumors than in normal tissues and longer in sarcomas and gliomas than in other cancers. Among 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications and transcript fusions and predictive of telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, characterized by undetectable TERT expression and alterations in ATRX or DAXX, demonstrated elongated telomeres and increased telomeric repeat-containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT nor harbored alterations in ATRX or DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.

Systematic analysis of telomere length and somatic alterations in 31 cancer types.

Synthetic lethality and collateral lethality are two well-validated conceptual strategies for identifying therapeutic targets in cancers with tumour-suppressor gene deletions. Here, we explore an approach to identify potential synthetic-lethal interactions by screening mutually exclusive deletion patterns in cancer genomes. We sought to identify 'synthetic-essential' genes: those that are occasionally deleted in some cancers but are almost always retained in the context of a specific tumour-suppressor deficiency. We also posited that such synthetic-essential genes would be therapeutic targets in cancers that harbour specific tumour-suppressor deficiencies. In addition to known synthetic-lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic-essential gene in PTEN-deficient cancers. In PTEN-deficient prostate and breast cancers, CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival and tumorigenic potential. Mechanistically, functional PTEN stimulates the GSK3β-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via the β-TrCP-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in stabilization of CHD1, which in turn engages the trimethyl lysine-4 histone H3 modification to activate transcription of the pro-tumorigenic TNF-NF-κB gene network. This study identifies a novel PTEN pathway in cancer and provides a framework for the discovery of 'trackable' targets in cancers that harbour specific tumour-suppressor deficiencies.

Synthetic essentiality of chromatin remodelling factor CHD1 in PTEN-deficient cancer.

Chinese liquor is one of the world's oldest distilled alcoholic beverages and an important commercial fermented product in China. The Chinese liquor fermentation process has three stages: making  (the starter), stacking fermentation on the ground, and liquor fermentation in pits. We investigated the bacterial diversity of Maotai and Guotai  and liquor fermentation using high-throughput sequencing of the V4 hypervariable region of the 16S rRNA gene. A total of 70,297 sequences were obtained from the  samples and clustered into 17 phyla. The composition of the bacterial communities in the  from these two soy sauce aroma-style Chinese liquors was the same, although some bacterial species changed in abundance. Between the  and liquor fermentation samples, 12 bacterial phyla increased. The abundance of  and  increased in the liquor fermentation. This study has used high-throughput sequencing to provide new insights into the bacterial composition of the Chinese liquor Daqu and fermentation. Similarities in the distribution of bacteria in the soy sauce aroma-style Chinese liquors  suggest that the abundance of bacteria might be generally concerned to other liquor.

Analysis of the Bacterial Communities in Two Liquors of Soy Sauce Aroma as Revealed by High-Throughput Sequencing of the 16S rRNA V4 Hypervariable Region.

Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma.

Gene fusion represents a class of molecular aberrations in cancer and has been exploited for therapeutic purposes. In this paper we describe TumorFusions, a data portal that catalogues 20 731 gene fusions detected in 9966 well characterized cancer samples and 648 normal specimens from The Cancer Genome Atlas (TCGA). The portal spans 33 cancer types in TCGA. Fusion transcripts were identified via a uniform pipeline, including filtering against a list of 3838 transcript fusions detected in a panel of 648 non-neoplastic samples. Fusions were mapped to somatic DNA rearrangements identified using whole genome sequencing data from 561 cancer samples as a means of validation. We observed that 65% of transcript fusions were associated with a chromosomal alteration, which is annotated in the portal. Other features of the portal include links to SNP array-based copy number levels and mutational patterns, exon and transcript level expressions of the partner genes, and a network-based centrality score for prioritizing functional fusions. Our portal aims to be a broadly applicable and user friendly resource for cancer gene annotation and is publicly available at http://www.tumorfusions.org.

TumorFusions: an integrative resource for cancer-associated transcript fusions.

Anthocyanins are distributed ubiquitously to terrestrial plants and chalcone isomerase (CHI) catalyzes the stereospecific isomerization of chalcones - a committed step in the anthocyanin biosynthesis pathway. In this study, one gene encoding CHI was isolated from  and designated as . Multiple sequence alignments and phylogenetic analysis revealed that OjCHI had the conserved CHI active site residues and was classified into type I CHI group. In order to better understand the mechanisms of anthocyanin synthesis in , integrative analysis between metabolites and  expression was conducted. The results showed  expression matched the accumulation patterns of anthocyanins not only in different tissues but also during the flower developmental stages, suggesting the potential roles of  in the biosynthesis of anthocyanin. Then biochemical analysis indicated that recombinant OjCHI protein exhibited a typical type I CHI activity which catalyzed the production of naringenin from naringenin chalcone. Moreover, expressing  in Arabidopsis  mutant restored the anthocyanins and flavonols phenotype of hypocotyl, cotyledon and seed coat, indicating its function as a chalcone isomerase . In summary, our findings reveal the  as well as  functions of OjCHI and provide a resource to understand the mechanism of anthocyanin biosynthesis in .

Chalcone Isomerase a Key Enzyme for Anthocyanin Biosynthesis in .

Exploration of native microbes is a feasible way to develop microbial agents for ecological restoration. This study was aimed to explore the impact of Bacillus amyloliquefaciens PDR1 from karst adaptive plant on the activity of root plasma membrane H-ATPase in Arabidopsis thaliana. A. thaliana was cultured in presence or absence of B. amyloliquefaciens PDR1 and its effects on the growth were evaluated by measuring the taproot length and dry weight. The rhizosphere acidification capacity was detected by a pH indicator, a pH meter and non-invasive micro-test techniques (NMT). The nutrient uptake was performed using appropriate methods. A combination of transcriptome sequencing and real-time quantitative polymerase chain reaction (qRT-PCR) was used to measure the expression of functional genes that regulate the plasma membrane H-ATPase activity in A. thaliana roots. Functional analysis was performed to understand how B. amyloliquefaciens regulates biological processes and metabolic pathways to strengthen A. thaliana resistance to alkaline stress. Here, we show that volatile organic compounds (VOCs) from B. amyloliquefaciens PDR1 promoted the growth and development of A. thaliana, enhanced the plasma membrane H-ATPase activity, and affected ion absorption in Arabidopsis roots. Moreover, B. amyloliquefaciens PDR1 VOCs did not affect the expression of the gene coding for plasma membrane H-ATPase, but affected the expression of genes regulating the activity of plasma membrane H-ATPase. Our findings illuminate the mechanism by which B. amyloliquefaciens regulates the growth and alkaline stress resistance of A. thaliana, and lay a foundation for wide and efficient application for agricultural production and ecological protection.

Bacillus amyloliquefaciens PDR1 from root of karst adaptive plant enhances Arabidopsis thaliana resistance to alkaline stress through modulation of plasma membrane H-ATPase activity.

Petal blight caused by fungi is among the most destructive diseases of Rhododendron, especially Rhododendron agastum. Nonetheless, the metabolite changes that occur during petal blight are unknown. We used untargeted gas chromatography time-of-flight mass spectrometry (GC-TOF-MS) and ultra-high performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UHPLC-QTOF-MS/MS) to compare the metabolite profiles of healthy and petal blight R. agastum flowers. Using GC-TOF-MS, 571 peaks were extracted, of which 189 metabolites were tentatively identified. On the other hand, 364 and 277 metabolites were tentatively identified in the positive and negative ionization modes of the UHPLC-QTOF-MS/MS, respectively. Principal component analysis (PCA) and orthogonal projections to latent structures-discriminant analysis (OPLS-DA) were able to clearly discriminate between healthy and petal blight flowers. Differentially abundant metabolites were primarily enriched in the biosynthesis of specialized metabolites. 17 accumulated specialized metabolites in petal blight flowers have been reported to have antifungal activity, and literature indicates that 9 of them are unique to plants. 3 metabolites (chlorogenic acid, medicarpin, and apigenin) are reportedly involved in resistance to blight caused by pathogens. We therefore speculate that the accumulation of chlorogenic acid, medicarpin, and apigenin may be involved in the resistance to petal blight. Our results suggest that these metabolites may be used as candidate biocontrol agents for the control fungal petal blight in Rhododendron.

Untargeted metabolite profiling of petal blight in field-grown Rhododendron agastum using GC-TOF-MS and UHPLC-QTOF-MS/MS.

Panicle degradation causes severe yield reduction in rice. There are two main types of panicle degradation: apical spikelet abortion and basal degeneration. In this study, we isolated and characterized the apical panicle abortion mutant  (), which exhibits degeneration and defects in the apical spikelets. This mutant had a pleiotropic phenotype, characterized by reduced plant height, increased tiller number, and decreased pollen fertility. Map-based cloning revealed that  encodes a boric acid channel protein that showed the highest expression in the inflorescence, peduncle, and anther. RNA-seq analysis of the  mutant vs wild-type (WT) plants revealed that biological processes related to reactive oxygen species (ROS) homeostasis and salicylic acid (SA) metabolism were significantly affected. Furthermore, the  mutants had an increased SA level and HO accumulation in the young panicles compared to the WT plants. Moreover, the SA level and the expression of , , and  genes (related to SA biosynthesis) were significantly increased under boron-deficient conditions in the  mutant and in knockout plants. Collectively, these results suggest that the boron distribution maintained by  is required for normal panicle development in a process that involves modulating ROS homeostasis and SA biosynthesis.

Ming Tang

Department of Genomic Medicine

University of Texas MD Anderson Cancer Center

An Integrated Platform for Genome-wide Mapping of Chromatin States Using High-throughput ChIP-sequencing in Tumor Tissues

Divergence of Root Microbiota in Different Habitats based on Weighted Correlation Networks

Ming Tang

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Genomic Medicine

University of Texas MD Anderson Cancer Center

An Integrated Platform for Genome-wide Mapping of Chromatin States Using High-throughput ChIP-sequencing in Tumor Tissues

Divergence of Root Microbiota in Different Habitats based on Weighted Correlation Networks

Department of Genomic Medicine