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Novel Bioinformatics Method for Identification of Genome-Wide Non-Canonical Spliced Regions using RNA-Seq Data

ABSTRACT: We developed a bioinformatics approach called the Read-Split-Walk (RSW) pipeline, and evaluated it using two Ire1? heterozygous and two Ire1?-null samples. The 26nt non-canonical splice site in Xbp1 was detected as the top hit by our RSW pipeline in heterozygous samples but not in the negative control Ire1? knockout samples. We compared the Xbp1 results from our approach with results using the alignment program BWA, STAR, Exonerate and the Unix “grep” command. We then applied our RSW pipeline to RNA-Seq data from the SKBR3 human breast cancer cell line. RSW reported a large number of non-canonical spliced regions for 108 genes in chromosome 17, which were identified by an independent study. Identification of non-canonical spliced regions for mouse MEF samples (two Ire1? heterozygous and two Ire1?-null samples)

ORGANISM(S): Mus musculus

SUBMITTER: Maureen Sartor

PROVIDER: E-GEOD-54631 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Novel Bioinformatics Method for Identification of Genome-Wide Non-Canonical Spliced Regions using RNA-Seq Data

Project description:We developed a bioinformatics approach called the Read-Split-Walk (RSW) pipeline, and evaluated it using two Ire1α heterozygous and two Ire1α-null samples. The 26nt non-canonical splice site in Xbp1 was detected as the top hit by our RSW pipeline in heterozygous samples but not in the negative control Ire1α knockout samples. We compared the Xbp1 results from our approach with results using the alignment program BWA, STAR, Exonerate and the Unix “grep” command. We then applied our RSW pipeline to RNA-Seq data from the SKBR3 human breast cancer cell line. RSW reported a large number of non-canonical spliced regions for 108 genes in chromosome 17, which were identified by an independent study.

2014-07-29 | GSE54631 | GEO

Natural killer cell proliferation requires canonical IRE1 function during viral infection (CITE-Seq)

Project description:The unfolded protein response (UPR) aims to restore ER homeostasis under conditions of high protein folding load, a function primarily serving secretory cells. Additional, non-canonical UPR functions have recently been unraveled in immune cells. We addressed the function of the inositol-requiring-enzyme 1 (IRE1) signaling branch of the UPR in NK cells in homeostasis and microbial challenge. Cell-intrinsic compound deficiency (DKO) of IRE1 and its downstream transcription factor XBP1 in NKp46 + NK cells, did not affect basal NK cell homeostasis, or overall outcome of viral MCMV infection. However, mixed bone marrow chimeras revealed a competitive advantage in the proliferation of IRE1 sufficient Ly49H + NK cells after viral infection. CITE-Seq analysis confirmed strong induction of IRE1 early upon infection, concomitant with the activation of a canonical UPR signature. Therefore, we conclude that cell-intrinsic IRE1/XBP1 activation is required for NK cell proliferation early upon viral infection, as part of a canonical UPR response.

2023-10-27 | GSE236820 | GEO

Natural killer cell proliferation requires canonical IRE1 function during viral infection (RNA-Seq)

2023-10-27 | GSE236819 | GEO

A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential

Project description:We report the effect on genome-wide gene expression after deletion of an enhancer region downstream of Sox2 in F1 ES cells. The Sox2 transcription factor must be robustly transcribed in embryonic stem (ES) cells to maintain pluripotency. Reporter assays reveal novel enhancers, including two enhancers over 100 kb downstream (SRR107 and SRR111) which, through the formation of chromatin loops, localise to the Sox2 promoter in ES cells. Using CRISPR/Cas9 we deleted a region containing these two enhancers, which we term the Sox2 control region (SCR). This deletion revealed that the SCR is required for Sox2 transcription in ES cells. Furthermore, homozygous deletion of this distal Sox2 control region (SCR) caused significant reduction in Sox2 mRNA and protein levels, loss of ES cell colony morphology, genome-wide changes in gene expression and impaired neuroectodermal formation upon spontaneous differentiation to embryoid bodies. Together these data identify a distal control region essential for Sox2 transcription in ES cells. Examination of PolA+ RNA after heterozygous and homozygous enhancer deletion in F1 ES cells (M. musculus129 x M. castaneus).

2014-11-19 | E-GEOD-58339 | biostudies-arrayexpress

A mechanistic rationale for targeting the unfolded protein response in pre-B acute lymphoblastic leukemia [HTS]

Project description:The plasma cell transcription factor XBP1 is critical for terminal differentiation of B cells into plasma cells but has no known role at earlier stages of B-cell development. Here we show that XBP1 is not only important during early B-cell development and for survival of pre-B cells but also protects pre-B ALL cells. Among pre-B ALL subset, XBP1 was hypomethylated and highest expressed in the Ph+ ALL subset. Cre-mediated deletion of XBP1 in a mouse model of Ph+ ALL compromised proliferation and viability and prolonged survival of leukemia-bearing mice. Interestingly, XBP1 expression levels were positively transcriptionally regulated by STAT5 and negatively by BACH2 and BCL6. High XBP1 expression in high risk ALL patients at the time of diagnosis predicted poor outcome in two clinical trials. Clinically, small-molecule inhibition of IRE1-dependent XBP1-activation caused cell death of patient-derived pre-B ALL cells and affected leukemia-initiation in transplant recipient mice. Collectively, these studies identify XBP1 as an important survival factor and as a potential therapeutic target to overcome drug-resistance in pre-B ALL. Genome-wide profiling of mRNA levels in p210 transduced murine Xbp1 fl/+ pre-B cells with ERT2 (XE.1,2,3) and Cre- ERT2 M-BM- (XC.1,2,3).

2014-04-24 | E-GEOD-53683 | biostudies-arrayexpress

The role of IRE1-XBP1 in RSV-mediated extracellular matrix production

Project description:This study is to examine the role of IRE1-XBP1 in regulation the activation of hexosamine biosynthetic pathway and N-glycosylation of extracellular matrix in RSV infection

2022-10-14 | PXD034780 | Pride

Expression data from IRE1a or XBP1 deficient mouse liver

Project description:IRE1a and XBP1 are key regulators of the unfolded protein response (UPR). XBP1 ablation causes profound hypolipidemia in mice, and triggers feedback activation of its upstream enzyme IRE1a, instigating regulated IRE1-dependent decay (RIDD), an mRNA degradation mechanism dependent on IRE1a's endoribonuclease activity. Comprehensive microarray analysis of XBP1 and/or IRE1a deficient liver identified genes involved in lipogenesis and lipoprotein metabolism as RIDD substrates, which might contribute to the suppression of plasma lipid levels by activated IRE1a. To identify RIDD substrate mRNAs and direct XBP1 targets in the liver, we performed a comprehensive comparative microarray analysis of three groups of RNA samples: WT and XBP1 deficient mice, WT and IRE1a deficient mice untreated or injected with tunicamycin, and XBP1 deficient mice injected with luciferase or IRE1a siRNA.

2012-10-17 | E-GEOD-40515 | biostudies-arrayexpress

Targeting the IRE1α/XBP1 endoplasmic reticulum stress response pathway in ARID1Amutant ovarian cancers

Project description:xenograft, patientderived xenograft and the genetic Arid1aflox/flox/Pik3caH1047R mouse models. Finally, B-I09 synergizes with inhibition of HDAC6, a known regulator of the ER stress response, in suppressing the growth of ARID1A-inactivated OCCCs. These studies reveal a promising therapeutic strategy for ARID1A-mutant OCCCs and define the IRE1?-XBP1 axis of the ER stress response as a targetable vulnerability for ARID1A-mutant OCCCs. Our findings indicate that pharmacological inhibition of the IRE1?-XBP1 pathway alone or in combination with HDAC6 inhibition represents an urgently needed therapeutic strategy for ARID1A-mutant ovarian cancers.

2021-08-10 | GSE180468 | GEO

Expression data from human multiple myeloma cells with or without IRE1-XBP1 silencing

Project description:We used microarrays to develop gene signatures for XBP1 and IRE1 in myeloma cells to explore the role of this UPR/differentiation pathway in proteasome inhibitor resistance.

2013-03-09 | GSE44968 | GEO

IRE1α-XBP1 sustains cytokine responses of group 3 innate lymphoid cells in inflammatory bowel disease

Project description:Group 3 innate lymphoid cells (ILC3s) are key players in intestinal homeostasis. Endoplasmic reticulum (ER) stress is linked to inflammatory bowel disease (IBD). Herein, we used cell culture, novel mouse models, and human specimens to examine if ER stress in ILC3s impacts IBD pathophysiology. We show that mouse intestinal ILC3s exhibited a 24h-rhythmic expression pattern of the master ER stress response regulator, IRE1α-XBP1. Proinflammatory cytokine IL-23 selectively stimulated IRE1α-XBP1 in mouse ILC3s through mitochondrial reactive oxygen species (mtROS). IRE1α-XBP1 was activated in ILC3s of mice exposed to experimental colitis and in inflamed human IBD specimens. Mice with Ire1α deletion in ILC3s (Ire1αΔRorc) showed reduced expression of ER stress response and cytokine genes including Il22 in ILC3s and were highly vulnerable to infections and colitis. Administration of IL-22 counteracted their colitis susceptibility. In human ILC3s, IRE1 inhibitors suppressed cytokine production, which was upregulated by an IRE1 activator. Moreover, the frequencies of intestinal XBP1s+ ILC3s in Crohn’s disease patients before administration of ustekinumab, an anti-IL-12/IL-23 antibody, positively correlated with response to treatment. We demonstrate that a non-canonical mtROS-IRE1α-XBP1 pathway augments cytokine production by ILC3s and identify XBP1+ ILC3s as a potential biomarker for predicting response to anti-IL-23 therapies in IBD. Group 3 innate lymphoid cells (ILC3s) have recently emerged as important regulators and potential drug targets for IBD. However, the response of ILC3s to environmental stimuli during intestinal inflammation remains elusive. IRE1a-XBP1 serves as the regulatory hub of the unfolded protein response (UPR) that plays a vital role in intestinal inflammation.

2024-05-31 | GSE261091 | GEO

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