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• Analysis of the Whole Transcriptomes of Human Testis with Complete Spermatogenesis and of Human Testes with Sertoli Cell-Only Syndrome

  Sertoli cell-only syndrome is severe form of human male infertility in which most seminiferous tubules appear to lack all spermatogenic cells, including spermatogonial stem cells (SSCs). However, a few small tubule segments of some patients have active spermatogenesis and, thus, functional stem cell niches and SSCs. Normally SSCs replicate, migrate and refill adjacent empty niches, but this does not appear to occur in SCO syndrome. We hypothesized that this failure occurs because most niches are dysfunctional. As Sertoli cells are essential to formation of these niches, we used RNAseq to compare the transcriptomes of human testes with qualitatively normal (complete) spermatogenesis (n=4) with the transcriptomes of human testes with SCO syndrome (n=7). We then focused our analysis on the expression of transcripts that bioinformatic analyses identified as Sertoli cell signature transcripts. Results show that Sertoli cells in SCO testes express abnormally low levels of GDNF, FGF8 and BMP4, all of which are important regulators of mouse SSCs and/or progenitor spermatogonia. Sertoli cells in SCO testes express significantly reduced levels of transcripts for proteins that polarize the Sertoli cell plasma membrane and regulate the trafficking of cell adhesion and gap junction proteins in and out of that plasma membrane.

  Study phs001777

• Stromal-induced epithelial-mesenchymal transition induces drug resistance in acute lymphoblastic leukemia

  Bone marrow (BM) microenvironment-induced drug resistance in acute lymphoblastic leukemia (ALL) is thought to be mediated by intercellular interaction of leukemic cells with BM niches, but the mechanistic basis of resistance is poorly understood. Here, we genomic and functional analyses, we show that ALL-BM mesenchymal stromal cells (MSC) interactions encompass direct cell-cell adhesion via integrin α4β1, uni-directional secretion of soluble factors from MSC to ALL, and bidirectional transfer of cellular vesicles through tunneling nanotubes. We show that this crosstalk drives an epithelial-mesenchymal transition (EMT)-like program in ALL cells adhering to MSC, thereby triggering stem cell-like features including drug resistance and survival advantage. Moreover, single-cell RNA sequencing of cell line and primary ALL samples identified a hybrid cell state derived from B-ALL adhered to MSC, that exhibits both B-ALL and MSC gene signatures that are orchestrated by an EMT-like program. Multiple EMT-activating pathways including WNT/β-catenin, cytokine/STAT3, TGFβ, NOTCH1, and NF-κB-dependent signaling pathways are activated in MSC-adherent ALL cells; however, only the inhibition of either WNT/β-catenin or cytokine/STAT3 pathway could attenuate the survival and drug resistance of ALL cells adherent to MSC. Notably, we identified that this hybrid cell state exhibited elevated WNT/β-catenin-mediated transcriptional activity. Finally, we show that blocking of the interaction of β-catenin and CBP interaction abrogates the survival and drug resistance of ALL cells adhered to MSC, indicating that targeting of an EMT-like program is potential therapeutic regimen in targeting cell extrinsically acquired drug resistance in ALL.

  Study EGAS00001006120

• Spatiotemporal evolution and inter-patient heterogeneity in primary and recurrent/metastatic head and neck squamous cell carcinoma

  Head and neck cancer squamous cell carcinomas (HNSCCs) are heterogeneous in terms of origin and aetiology. In addition, there is uncertainty about the spatiotemporal genetic evolution from initial diagnosis to recurrence/metastasis (R/M) after primary treatments and further disease progression following systemic treatment. Changes in the genetic profile have implications on the selection of appropriate treatments for patients, especially in the era of targeted therapies and immunotherapies. Here, we analysed a cohort of 11 HNSCC patients with metachronous R/M, among whom nine had paired primary and R/M samples suitable for next-generation sequencing (multiple R/M samples collected at different time points were available for some of the patients). At the genomic level, the R/M samples shared a fraction of the somatic single nucleotide variants (SNVs) with the index primary tumours, but they also acquired many additional mutations, while losing only a few others. A similar behaviour was also observed when examining the changes of mutational signatures between primary and R/M samples. Overall, R/M appeared thus more genetically diverse than the respective primary tumours. The transcriptomic analysis showed that R/M samples had lower immune cell infiltration and several genes related to immune response were significantly downregulated compared to the primary samples. Our results underline the importance of analysing multiple samples per patient to obtain a more complete picture of the patient’s tumour and advocates a re-biopsy in the event of R/M and treatment failure, in order to select the most appropriate therapeutic strategy.

  Study EGAS00001007464

• Widespread hypertranscription in aggressive human cancers

  Cancers are often defined by the dysregulation of specific transcriptional programs; however, the importance of global transcriptional changes is less understood. Hypertranscription is the genome-wide increase in RNA output. Hypertranscription’s prevalence, underlying drivers and prognostic significance are undefined in primary human cancer. This is due in part to limitations of expression profiling methods, which assume equal RNA output between samples. Here, we developed a computational method to directly measure hypertranscription in 7,494 human tumors, spanning 31 cancer types. Hypertranscription is ubiquitous across cancer, especially in aggressive disease. It defines patient subgroups with worse survival, even within well-established subtypes. Our data suggest that loss of transcriptional suppression underpins the hypertranscriptional phenotype. Single-cell analysis reveals hypertranscriptional clones, which dominate transcript production regardless of their size. Finally, patients with hypertranscribed mutations have improved response to immune checkpoint therapy. Our results provide fundamental insights into gene dysregulation across human cancers and may prove useful in identifying patients that would benefit from novel therapies.

  Study EGAS00001006365

• Muscle SATellite cell study (MSAT)

  Skeletal muscle fiber type distribution has implications for human health, muscle function and performance. This knowledge has been gathered using labor-intensive and costly methodology that limited these studies. This data was used to present a new method based on muscle tissue RNA sequencing data to estimate the distribution of skeletal muscle fiber types from frozen human samples, allowing for larger number of individuals to be tested in a cost and labor efficient way. Muscle biopsies were taken from the vastus lateralis muscle of 39 Swedish male subjects. Samples were sequenced on the NextSeq® 500/550 (Illumina).

  Study EGAS00001006363

• Juntendo Muscle Study (JMS)

  Skeletal muscle fiber type distribution has implications for human health, muscle function and performance. This knowledge has been gathered using labor intensive and costly methodology that limited these studies. This data was used to present a new method based on muscle tissue RNA sequencing data to estimate the distribution of skeletal muscle fiber types from frozen human samples, allowing for larger number of individuals to be tested in a cost and labor efficient way. Muscle biopsies were taken from the vastus lateralis muscle of 23 human subjects from Japan. Samples were sequenced on the NextSeq® 500/550 (Illumina).

  Study EGAS00001006362

• An allele-resolved nanopore-guided tour of the human placental methylome

  The placenta is a temporary organ present during pregnancy that is responsible for coordinating all aspects of pregnancy between the mother and fetus. It has a distinct epigenetic, transcriptomic, and mutational landscape with low levels of methylation, high numbers of transcribed loci, and a high mutational burden relative to somatic tissues. We present this landscape through the application of nanopore sequencing technology to provide a more comprehensive picture of female placental genomics and methylomics along with integrated haplotype-resolved transcriptomic analyses across eight trios. Whole genome sequencing of trios allows robust phasing, permitting comprehensive genome-wide investigation of parent-of-origin methylation and transcription. This enhanced view facilitates identifications of many new differentially methylated regions (DMRs), both conserved and differing between individuals, as well as novel imprinted genes.

  Study EGAS50000001301

• Mobile Technology to Identify Mechanisms Linking Genetic Variation and Depression in Intern Health Study (IHS)

  The Intern Health Study is an NIH-funded longitudinal cohort study that assesses stress and mood in medical interns at institutions around the US, enrolling over 3000 new interns each year. We are hopeful that data collected in this study will further understanding of the psychological, genetic, and program factors involved in the development of depression under stress, and make a real change in the residency experience.

  Study phs001826

• CRC Promoter capture Hi-C

  Genome organisation determines chromosome interactions between regulatory elements, such as promoters and enhancers, influencing gene expression. Despite the fact that it is possible to assess whether a gene is actively transcribed, it has been challenging to point out the genomic regions that are involved in the regulation of a particular gene. We are interested in better understanding the interactions between promoters and their regulatory elements in colorectal cancer in order to unveil novel non-coding regions which might have a role in tumour development. To do so, we utilise the HiC method complemented with promoter capture in combination with NGS to map promoter interactions in two CRC cell lines, representing two distinct CRC subtypes.

  Study EGAS00001001946

• Multi-omics analysis of treated cancer samples

  We treated patient-derived cell lines with effective drug inhibitors that we discovered. To understand the mechanisms behind how the inhibitor can effectively inhibit tumor growth, we performed a series of RNA-Seq, Histone ChIP-Seq, TF ChIP-Seq and ATAC-Seq profiling for samples with and without treatment with the inhibitor. There are 18 RNA-Seq, 20 ATAC-Seq and 182 ChIP-Seq experiments performed. This includes 2 biological replicates. Novaseq 6000 was used to sequence the samples. Library preparation was performed in house for ChIP-Seq and ATAC-Seq, using NEB indexes, while libraries for RNA-Seq were constructed by the sequencing company hired. Total RNA was sequenced. Sequencing parameters used are PE150, bi-directional sequencing. For ATAC-Seq, sequencing was performed up to 40M reads, for ChIP-Seq, sequencing was performed up to 20M reads and for RNA-Seq, sequencing was performed up to 20M to 40M reads. Fastq files are uploaded here.

  Dataset EGAD50000000349