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.

Pseudotumoral calcinosis in systemic sclerosis: Data from systematic literature review and case series from two referral centres.

OBJECTIVES: We aimed to clarify the definition, distribution, clinical association and outcomes of large calcinosis in patients with systemic sclerosis (SSc). METHODS: We conducted a systematic literature review (SLR) focusing on SSc-related large calcified masses. Upon updating the terminology and definition, all cases of "pseudotumoral" calcinosis seen at the Cochin and Padova University Hospitals were reviewed. RESULTS: The SLR yielded 30 SSc cases, with large calcified masses mainly defined as "tumoral" or "pseudotumoral". Among the 629 SSc cases included in the Cochin and Padova cohorts, 19 (3%) living and 7 deceased patients were affected by pseudotumoral calcinosis; among these, the great majority had a severe vascular phenotype. The mean age in the whole population (56 cases) was 59 ± 11.4 years with a median disease duration at calcinosis onset of 7 (5-10) years. Twenty-five out of 56 patients (44.6%) had the diffuse cutaneous form of SSc. Anti-topisomerase I and anticentromere were found equally. Pseudotumoral calcinosis were commonly symmetrical and the size ranged from 2 to 15.5 cm. Most patients had multiple site involvement: 52% hand/wrist, 29% shoulders and elbows, 20% hips and 25% spinal calcinosis. Fistulization/ulceration and infections were reported in 32% and 23% of cases, respectively; nerve compression was found in 40% of spinal calcinosis and in one patient with limb calcinosis. There was no clear evidence of clinical and radiological improvement with any treatment. A partial improvement was seen in 7 patients that underwent surgery. CONCLUSION: Pseudotumoral calcinosis may occur in about 3% of SSc patients, commonly symmetrical and in multiple sites without differences regarding the cutaneous subtypes but often in those with a severe vascular phenotype. Medical treatment seems ineffective, whereas a surgical approach may be considered.

Spectrum-based de novo repeat detection in genomic sequences.

A novel approach to the detection of genomic repeats is presented in this paper. The technique, dubbed SAGRI (Spectrum Assisted Genomic Repeat Identifier), is based on the spectrum (set of sequence k-mers, for some k) of the genomic sequence. Specifically, the genome is scanned twice. The first scan (FindHit) detects candidate pairs of repeat-segments, by effectively reconstructing portions of the Euler path of the (k-1)-mer graph of the genome only in correspondence with likely repeat sites. This process produces candidate repeat pairs, for which the location of the leftmost term is unknown. Candidate pairs are then subjected to validation in a second scan, in which the genome is labelled for hits in the (much smaller) spectrum of the repeat candidates: high hit density is taken as evidence of the location of the first segment of a repeat, and the pair of segments is then certified by pairwise alignment. The design parameters of the technique are selected on the basis of a careful probabilistic analysis (based on random sequences). SAGRI is compared with three leading repeat-finding tools on both synthetic and natural DNA sequences, and found to be uniformly superior in versatility (ability to detect repeats of different lengths) and accuracy (the central goal of repeat finding), while being quite competitive in speed. An executable program can be downloaded at http://sagri.comp.nus.edu.sg.