An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells.

The aberrant activities of transcription factors such as the androgen receptor (AR) underpin prostate cancer development. While the AR cis-regulation has been extensively studied in prostate cancer, information pertaining to the spatial architecture of the AR transcriptional circuitry remains limited. In this paper, we propose a novel framework to profile long-range chromatin interactions associated with AR and its collaborative transcription factor, erythroblast transformation-specific related gene (ERG), using chromatin interaction analysis by paired-end tag (ChIA-PET). We identified ERG-associated long-range chromatin interactions as a cooperative component in the AR-associated chromatin interactome, acting in concert to achieve coordinated regulation of a subset of AR target genes. Through multifaceted functional data analysis, we found that AR-ERG interaction hub regions are characterized by distinct functional signatures, including bidirectional transcription and cotranscription factor binding. In addition, cancer-associated long noncoding RNAs were found to be connected near protein-coding genes through AR-ERG looping. Finally, we found strong enrichment of prostate cancer genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) at AR-ERG co-binding sites participating in chromatin interactions and gene regulation, suggesting GWAS target genes identified from chromatin looping data provide more biologically relevant findings than using the nearest gene approach. Taken together, our results revealed an AR-ERG-centric higher-order chromatin structure that drives coordinated gene expression in prostate cancer progression and the identification of potential target genes for therapeutic intervention.

Recurrent Fusion Genes in Gastric Cancer: CLDN18-ARHGAP26 Induces Loss of Epithelial Integrity.

Genome rearrangements, a hallmark of cancer, can result in gene fusions with oncogenic properties. Using DNA paired-end-tag (DNA-PET) whole-genome sequencing, we analyzed 15 gastric cancers (GCs) from Southeast Asians. Rearrangements were enriched in open chromatin and shaped by chromatin structure. We identified seven rearrangement hot spots and 136 gene fusions. In three out of 100 GC cases, we found recurrent fusions between CLDN18, a tight junction gene, and ARHGAP26, a gene encoding a RHOA inhibitor. Epithelial cell lines expressing CLDN18-ARHGAP26 displayed a dramatic loss of epithelial phenotype and long protrusions indicative of epithelial-mesenchymal transition (EMT). Fusion-positive cell lines showed impaired barrier properties, reduced cell-cell and cell-extracellular matrix adhesion, retarded wound healing, and inhibition of RHOA. Gain of invasion was seen in cancer cell lines expressing the fusion. Thus, CLDN18-ARHGAP26 mediates epithelial disintegration, possibly leading to stomach H(+) leakage, and the fusion might contribute to invasiveness once a cell is transformed.

TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome.

Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a highly malignant neoplasm of bone belonging to the spectrum of LFS tumors. Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription. Screening of 288 OS and 1,090 tumors of other types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were detected in other tumor types, indicating this rearrangement to be highly specific to OS. We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere. The inversion segregated with tumors in the LFS family. Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss. In conclusion, intron 1 rearrangements cause p53-driven malignancies by both germline and somatic mechanisms and provide an important mechanism of TP53 inactivation in LFS, which might in part explain the diagnostic gap of formerly classified "TP53 wild-type" LFS.

Differential transcriptomic analyses revealed genes and signaling pathways involved in iono-osmoregulation and cellular remodeling in the gills of euryhaline Mozambique tilapia, Oreochromis mossambicus.

BACKGROUND: The Mozambique tilapia Oreochromis mossambicus has the ability to adapt to a broad range of environmental salinities and has long been used for investigating iono-osmoregulation. However, to date most studies have focused mainly on several key molecules or parameters hence yielding a limited perspective of the versatile iono-osmoregulation in the euryhaline fish. This study aimed to capture transcriptome-wide differences between the freshwater- and seawater-acclimated gills of the Mozambique tilapia. RESULTS: We have identified over 5000 annotated gene transcripts with high homology (E-value <1.0E-50) to human genes that were differentially expressed in freshwater- and seawater-acclimated gills of the Mozambique tilapia. These putative human homologs were found to be significantly associated with over 50 canonical signaling pathways that are operating in at least 23 biological processes in relation to branchial iono-osmoregulation and cellular remodeling. The analysis revealed multiple signaling pathways in freshwater-acclimated gills acting in concert to maintain cellular homeostasis under hypo-osmotic environment while seawater-acclimated gills abounded with molecular signals to cope with the higher cellular turn-over rate, energetics and iono-regulatory demands under hyper-osmostic stress. Additionally, over 100 transcripts encoding putative inorganic ion transporters/channels were identified, of which several are well established in gill iono-regulation while the remainder are lesser known. We have also validated the expression profiles of 47 representative genes in freshwater- and seawater-acclimated gills, as well as in hypersaline-acclimated (two-fold salinity of seawater) gills. The findings confirmed that many of these responsive genes retained their expression profiles in hypersaline-acclimated gills as in seawater-acclimated gills, although several genes had changed significantly in their expression level/direction in hypersaline-acclimated gills. CONCLUSIONS: This is the first study that has provided an unprecedented transcriptomic-wide perspective of gill iono-osmoregulation since such studies were initiated more than 80 years ago. It has expanded our molecular perspective from a relatively few well-studied molecules to a plethora of gene transcripts and a myriad of canonical signaling pathways driving various biological processes that are operating in gills under hypo-osmotic and hyper-osmotic stresses. These findings would provide insights and resources to fuel future studies on gill iono-osmoregulation and cellular remodeling in response to salinity challenge and acclimation.

UASIS: Universal Automatic SNP Identification System.

BACKGROUND: SNP (Single Nucleotide Polymorphism), the most common genetic variations between human beings, is believed to be a promising way towards personalized medicine. As more and more research on SNPs are being conducted, non-standard nomenclatures may generate potential problems. The most serious issue is that researchers cannot perform cross referencing among different SNP databases. This will result in more resources and time required to track SNPs. It could be detrimental to the entire academic community. RESULTS: UASIS (Universal Automated SNP Identification System) is a web-based server for SNP nomenclature standardization and translation at DNA level. Three utilities are available. They are UASIS Aligner, Universal SNP Name Generator and SNP Name Mapper. UASIS maps SNPs from different databases, including dbSNP, GWAS, HapMap and JSNP etc., into an uniform view efficiently using a proposed universal nomenclature and state-of-art alignment algorithms. UASIS is freely available at http://www.uasis.tk with no requirement of log-in. CONCLUSIONS: UASIS is a helpful platform for SNP cross referencing and tracking. By providing an informative, unique and unambiguous nomenclature, which utilizes unique position of a SNP, we aim to resolve the ambiguity of SNP nomenclatures currently practised. Our universal nomenclature is a good complement to mainstream SNP notations such as rs# and HGVS guidelines. UASIS acts as a bridge to connect heterogeneous representations of SNPs.

[Expression of nm23 H(1) gene in childhood acute lymphoblastic leukemia and the relationship between nm23 H(1) expression and immunophenotype].

OBJECTIVE: To study the expression of nm23-H(1) gene in children with acute lymphoblastic leukemia (ALL) and the relationship between nm23-H(1) expression and immunophenotype. METHODS: nm23-H(1) expression was measured by semiquantitative RT-PCR in children with ALL (newly diagnosed, n = 40; remission, n = 32; relapse, n = 16; refractory, n = 3). Twenty normal children served as the control group. The relationship between nm23-H(1) expression and immunophenotype was evaluated. RESULTS: The expression of nm23-H(1) in the newly diagnosed ALL group was significantly higher than that in the control (p<0.01) and the remission groups (p<0.01). There was no difference in the nm23-H(1) expression between the remission and the control groups. The expression of nm23-H(1) in the relapse group was significantly higher than that in the control (p<0.01) and the remission groups (p<0.01), and similar to that in the newly diagnosed ALL group. The three children with refractory ALL had higher nm23-H(1) expression. Both the positive rate and expression of nm23-H(1) in children with T-lineage ALL were higher than in children with B-lineage ALL (p<0.05). CONCLUSIONS: The expression level of nm23-H(1) varies with the stages of ALL. Newly diagnosed, relapsed and refractory ALL children have higher nm23-H(1) expression. High nm23-H(1) expression may be associated with a poor prognosis and relapse. A higher expression of nm23-H(1) in children with T-ALL may be contributed to a low remission rate and a poor prognosis.