DDX17 (P72), a Sox2 binding partner, promotes stem-like features conferred by Sox2 in a small cell population in estrogen receptor-positive breast cancer

Alqahtani, Hind; Gopal, Keshav; Gupta, Nidhi; Jung, Karen; Alshareef, Abdulraheem; Ye, X; Wu, Fang; Li, L; Lai, Raymond

doi:10.1016/j.cellsig.2015.11.004

Cited by 30 publications

(31 citation statements)

References 32 publications

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“…In the frontal cortex, nearly 70% of trans-eQTLs were located within the MHC locus on chromosome 6p21 and were associated with expression of DDX17 on chromosome 22q13.1, which encodes for a RNA-binding protein. While the specific role of this protein, also known as p72, in brain is still uncertain, it is involved in numerous aspects of RNA metabolism, including promoting microRNA biogenesis and reducing viral RNA stability 36, 37 DDX17 is also a binding-partner to the transcription factor SOX2 38 , thereby potentially influencing master regulation of gene expression.…”

Section: Resultsmentioning

confidence: 99%

Identification of Brain Expression Quantitative Trait Loci Associated with Schizophrenia and Affective Disorders in Normal Brain Tissue

Bhalala

Nath

Inouye

et al. 2016

Preprint

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Schizophrenia and the affective disorders, here comprising bipolar disorder and major depressive disorder, are psychiatric illnesses that lead to significant morbidity and mortality worldwide. Whilst understanding of their pathobiology remains limited, large case-control studies have recently identified single nucleotide polymorphisms (SNPs) associated with these disorders. However, discerning the functional effects of these SNPs has been difficult as the associated causal genes are unknown. Here we evaluated whether schizophrenia and affective disorder associated-SNPs are correlated with gene expression within human brain tissue. Specifically, to identify expression quantitative trait loci (eQTLs), we leveraged disorder-associated SNPs identified from six Psychiatric Genomics Consortium and CONVERGE Consortium studies with gene expression levels in post-mortem, neurologically-normal tissue from two independent human brain tissue expression datasets (UK Brain Expression Consortium (UKBEC) and Genotype-Tissue Expression (GTEx)). We identified 6 188 and 16 720 cis-acting SNPs exceeding genome-wide significance (p<5x10 -8 ) in the UKBEC and GTEx datasets, respectively. 1 288 cis-eQTLs were significant in a metaanalysis leveraging overlapping brain regions and were associated with expression of 15 genes, including three non-coding RNAs. One cis-eQTL, rs16969968, results in a functionally disruptive missense mutation in CHRNA5, a schizophrenia-implicated gene.Meta-analysis identified 297 trans-eQTLs associated with 24 genes that were significant in a region-specific manner. Importantly, comparing across tissues, we find that blood eQTLs largely do not capture brain cis-eQTLs. This study identifies putatively causal genes whose expression in region-specific brain tissue may contribute to the risk of schizophrenia and affective disorders. downloaded from the PGC website (https://www.med.unc.edu/pgc). SNPs were collated from the following studies: PGC-SCZ2 4 for schizophrenia, PGC-BIP 5 and PGC-MooDs 6 for bipolar disorder, PGC-MDD 7 and CONVERGE 8 for major depressive disorder, and PGC-Cross Disorder Analysis 9 for multiple disorders (schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder and attention-deficit hyperactivity disorder).Of note, PGC-MooDs analysis included samples from the PGC-BIP study; PGC-Cross Disorders analysis included samples from the PGC-SCZ2, PGC-BIP and PGC-MDD studies.We included overlapping studies to maximize the number of disorder-associated SNPs in our analysis as there may be loci identified in one study but not in another.SNPs with a study p-value < 5 x 10 -5 were included in the analysis. For SNPs from all studies except PGC-SCZ2, we also obtained SNPs that are in moderate-high linkage disequilibrium (LD, R 2 ≥ 0.5) with the study-SNPs 31 using the web-based tool rAggr (http://raggr.usc.edu/). LD-analysis settings were as follows: CEU population from 1000 Genomes Phase 3 October 2014 release, build hg19, minimum minor allele frequency = 0.001, maximum distanc...

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Section: Resultsmentioning

confidence: 99%

Identification of Brain Expression Quantitative Trait Loci Associated with Schizophrenia and Affective Disorders in Normal Brain Tissue

Bhalala

Nath

Inouye

et al. 2016

Preprint

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“…All immunoprecipitation (IP) experiments were carried out using all received 6 clones: 4C7G2, 4C7G6, 4C7H7, 4C7A4, 4C7A5 and 4C7D8 (2 µg) with 500 µg cell lysate collected in ice-cold RIPA buffer (Cell Signaling Technologies, Danvers, MA, USA) supplemented with protease and phosphatase inhibitors (EMD Millipore, Etobicoke, ON, Canada) as described previously [ 19 ]. Peptide dot blotting was carried out using phospho-Sox2 T116 specific immunizing peptide and the unphopshporylated Sox2 peptide as follows 0.05, 0.1, 0.2, 0.5, 1 and 2 µg peptide diluted in PBS was directly pipetted onto nitrocellulose membrane and allowed to dry.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features

Gupta

Gopal

et al. 2018

Cancers

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We have previously identified a novel phenotypic dichotomy in breast cancer (BC) based on the response to a SRR2 (Sox2 regulatory region 2) reporter, with reporter responsive (RR) cells being more tumorigenic/stem-like than reporter unresponsive (RU) cells. Since the expression level of Sox2 is comparable between the two cell subsets, we hypothesized that post-translational modifications of Sox2 contribute to their differential reporter response and phenotypic differences. By liquid chromatography-mass spectrometry, we found Sox2 to be phosphorylated in RR but not RU cells. Threonine 116 is an important phosphorylation site, since transfection of the T116A mutant into RR cells significantly decreased the SRR2 reporter luciferase activity and the RR-associated phenotype. Oxidative stress-induced conversion of RU into RR cells was accompanied by Sox2 phosphorylation at T116 and increased Sox2-DNA binding. In a cohort of BC, we found significant correlations between the proportion of tumor cells immuno-reactive with anti-phosphorylated Sox2T116 and a high tumor grade (p = 0.006), vascular invasion (p = 0.001) and estrogen receptor expression (p = 0.032). In conclusion, our data suggests that phosphorylation of Sox2T116 contributes to the tumorigenic/stem-like features in RR cells. Detection of phospho-Sox2T116 may be useful in identifying a small subset of tumor cells carrying stem-like/tumorigenic features in BC.

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“…Moreover, RT-PCR analysis showed a significant age-dependent dysregulation in expression of several genes (Supplemental Table 4), indicating that age of disease onset may affect DCM phenotype in pediatric patients. Expression of dysregulated genes was filtered to detect genes specifically involved in signal transduction; enrichment of genes involved in cell cycle progression and pluripotency stem cell signalling was observed (Table 2) and include CCND1 (P = 0.0023) (22), CCND2 (P = 0.00025) (22), CUX1 (P = 0.00468) (23), kinesin-like protein 22 (KIF22) (P = 0.006) (24), chromobox protein homologue 7 (CBX7) (P = 0.0057) (25), KLF2 (P = 0.003) (26), HMGB2 (P = 0.043) (27), and DDX17 (P = 0.05) (28). Additionally, TBX5 (P = 0.015) and GATA6 (P = 0.0038) were upregulated, both of which have been implicated in reprogramming of pluripotent stem cells (13,29).…”

Section: Discussionmentioning

confidence: 99%

Pediatric dilated cardiomyopathy hearts display a unique gene expression profile

et al. 2017

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DDX17 (P72), a Sox2 binding partner, promotes stem-like features conferred by Sox2 in a small cell population in estrogen receptor-positive breast cancer

Cited by 30 publications

References 32 publications

Identification of Brain Expression Quantitative Trait Loci Associated with Schizophrenia and Affective Disorders in Normal Brain Tissue

Identification of Brain Expression Quantitative Trait Loci Associated with Schizophrenia and Affective Disorders in Normal Brain Tissue

Phosphorylation of Sox2 at Threonine 116 is a Potential Marker to Identify a Subset of Breast Cancer Cells with High Tumorigenecity and Stem-Like Features

Pediatric dilated cardiomyopathy hearts display a unique gene expression profile

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