DOCSLIB.ORG

SOX9 Interacts with FOXC1 to Activate MYC and Regulate CDK7 Inhibitor

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
SOX9 Interacts with FOXC1 to Activate MYC and Regulate CDK7 Inhibitor Tang et al. Oncogenesis (2020) 9:47 https://doi.org/10.1038/s41389-020-0232-1 Oncogenesis ARTICLE Open Access SOX9 interacts with FOXC1 to activate MYC and regulate CDK7 inhibitor sensitivity in triple-negative breast cancer Lin Tang1,JuanJin1,2,KunXu3,XinWang1,JinhaiTang 4 and Xiaoxiang Guan1,3 Abstract Triple-negative breast cancer (TNBC) is particularly sensitive to cyclin-dependent kinase 7 inhibitor, THZ1, compared to hormone receptor (HR)+ breast cancer, but our data found that different TNBC cell lines had a wide range of IC50 values of THZ1, suggesting a possible heterogeneity in sensitivity to THZ1 in TNBC. To seek potential biomarkers of THZ1 sensitivity, we re-analyzed the mRNAs profile in breast cancer cells treated with THZ1 from the previous study and demonstrated that elevated expression of SOX9 was significantly associated with the sensitivity of THZ1 in TNBC. We also verified that SOX9 expression promoted cell proliferation, migration, stemness, and predicted poor prognosis. Moreover, based on the tissue array of 278 patients and over 900 samples from TCGA data, we found that SOX9 expression was significantly higher in TNBC than HR+ breast cancers. Furthermore, ChIP-sequencing indicated that SOX9 binding to enhancer near transcription factor FOXC1, was remarkably inhibited by THZ1. And we also demonstrated that SOX9 and FOXC1 interacted with each other, which might co-operate and co-regulate the MYC signaling pathway in TNBC. Mechanistically, SOX9 may sensitize TNBC cells to THZ1, in a FOXC1-related manner, suggesting that SOX9 could be as a predictive factor of THZ1. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction cluster of particular genes, which are overexpressed in Triple-negative breast cancer (TNBC) is a particularly TNBC but not in hormone receptor (HR)+ breast cancer aggressive subtype of breast cancer, which is characterized cells containing putative oncogenes, promoting TNBC by high genetic complexity and lacks the distinct driver tumorigenicity and the disease development3. Moreover, oncogenes1. Because of the tumor heterogeneity of an excessive number of genes in this cluster are associated TNBC, the development of targeted therapies has been with super-enhancers (SEs)4,5. It is commonly accepted limited for a long time2. Surprisingly, a recent research that enhancers are regions of non-coding DNA, which identifies that TNBC is selectively sensitive to THZ1, a mediate the transcription of adjacent genes, serving as a newly developed CDK7 inhibitor3. Recent studies have cis-regulatory element6. SEs are a subset of the enhancers found that besides the regulation of cell cycle, CDK7 is with a pronounced effect on recruiting transcription fac- also essential in promoting transcription processes. CDK7 tors, cofactors, and chromatin regulators to drive the inhibitor can strongly diminish the transcription of a abundant expression of some significant oncogenes, such as MYC, CCND2, and EGFR, in various tumors. CDK7 inhibitor is expected to control TNBC cell proliferation by Correspondence: Jinhai Tang ([email protected])or inhibiting the super-enhancer-associated oncogenes3. Xiaoxiang Guan ([email protected]) 1Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing Although TNBC have showed an extreme sensitivity to University, Nanjing 210002, China THZ1 compared to HR+ breast cancer, different 2 Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai responses to the CDK7 inhibitor still exist among differ- 200032, China Full list of author information is available at the end of the article ent TNBC cell lines shown by us and Wang and These authors contributed equally: Lin Tang, Juan Jin, Kun Xu © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Oncogenesis Tang et al. Oncogenesis (2020) 9:47 Page 2 of 12 coworkers3. Therefore, to identify the factors that predict time-dependent manner (Fig. 1d), we focused further on against the THZ1 response in TNBC may help with a SOX9 that has not been evaluated deeply in TNBC. better selection of TNBC patients for the treatment. Moreover, in a panel of TNBC cell lines with varying Previous studies found that THZ1 elicited selective effects levels of SOX9 expression, SOX9 expression levels were mainly by hampering highly active transcription and negative with IC50 values, and SOX9-amplified cells had a preferentially induced selective inactivation of super- high sensitivity to THZ1, indicating that SOX9 would be a enhancer-associated oncogenes4,5,7,8. If some oncogenic predictive factor for the THZ1 sensitivity (Fig. 1e, f). Next, transcription factors are associated with SEs, malignant we silenced SOX9 in MDA-468 and BT549 but over- potency of the transcription factors will be amplified, expressed SOX9 in MDA-157 that had a relatively low which can trigger numerous and deregulate transcription baseline expression level of SOX9. We found that SOX9 processes in tumors. So, we focused on the super- knockdown increased the IC50 values in MDA-468 and enhancer-associated transcription factors and demon- BT549, while ectopic expression of SOX9 in MDA-157 strated that SOX9, which is a super-enhancer-associated sensitized cells to THZ1 (Fig. 1g). Together, these results transcription factor in TNBC cells, predicted the sensi- showed that the SOX9 expression level was positively tivity of TNBC to THZ1. Most of the published studies associated with the sensitivity to THZ1 in TNBC cells. reported that SOX9 as an oncogenic protein was over- expressed in various solid tumors, inducing cancer cell SOX9 facilitated malignant properties in TNBC cells – growth, proliferation, migration, and invasion9 14. More- Although numerous studies have investigated the roles over, co-expression of exogenous Slug and Sox9 increased of SOX9 in cancers of the prostate and colorectum10,12,14, the tumorigenic and metastatic abilities of breast cancer few investigated molecular functions of SOX9 in breast cells and was associated with poor outcomes in breast cancer. As shown in Supplementary Fig. S1, the cell cancer patients11. In the present study, we demonstrated proliferation, colony formation and migration ability of that high SOX9 expression was associated with malignant TNBC cells treated with THZ1 were significantly phenotype in both TNBC cells and TNBC patients. decreased, compared to the control group. To adequately However, the exact mechanisms underlying SOX9 func- address the mechanisms underlying the functional asso- tions during tumor formation and development largely ciation between SOX9 and CDK7 inhibitor, we investi- remain unclear until now. Here, we are the first to gated the biological functions of SOX9 in TNBC cells. demonstrate the roles of SOX9 in TNBC and the possible Colony formation assay showed that SOX9 silence dis- mechanisms of its predictive role in the THZ1 sensitivity. tinctly inhibited cell proliferation, while SOX9 over- expression promoted cell proliferation (Fig. 2a). We also Results investigated the effect of SOX9 on cell migration in TNBC SOX9 predicted sensitivity to THZ1 in TNBC cells cells and showed that SOX9 inhibition weakened the We demonstrated that THZ1 treatment indeed showed migration potential of MDA-468 and BT549. In contrast, strong cytotoxicity in TNBC cell lines, consistent with a the forced overexpression of SOX9 promoted cell previously published study3, but we also observed that migration in MDA-157 (Fig. 2b, c). some TNBC cell lines, such as BT-20 and MDA-157, were Because several studies have identified SOX9 as an not sensitive to THZ1 (Fig. 1a). Notably, the most important stem cell marker, we tested the effect of SOX9 11 insensitive cell lines were with IC50 values averaging on tumorsphere formation . SOX9 knockdown sup- almost ten times higher than those of sensitive ones pressed tumor-initiating ability with less tumorsphere (Fig. 1a), which hint that there are probably some factors formation compared to the control group. However, a responsible for the THZ1 efficacy in TNBC cells. We statistic difference was not observed between MDA-157 analyzed the gene expression values of super-enhancer- and MDA-157 with SOX9 overexpression (Fig. 2d). Pre- associated transcription factors based on the microarray vious studies showed that epithelial-mesenchymal tran- data of two TNBC cell lines and two HR+ breast cancer sition (EMT) progresses supported the stemness of cancer cell lines treated with THZ1 from the previously pub- cells and regulated cell migration ability15. As shown in lished study3 (Fig. 1b). The ideal predictive factor is Fig. 2e, knockdown of SOX9 significantly increased the identified as elevated in TNBC cells compared to HR+ expression levels of the epithelial marker
Load more

Recommended publications
  • A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
    Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated.
    [Show full text]
  • The Forkhead-Box Family of Transcription Factors: Key Molecular Players in Colorectal Cancer Pathogenesis Paul Laissue
    Laissue Molecular Cancer (2019) 18:5 https://doi.org/10.1186/s12943-019-0938-x REVIEW Open Access The forkhead-box family of transcription factors: key molecular players in colorectal cancer pathogenesis Paul Laissue Abstract Colorectal cancer (CRC) is the third most commonly occurring cancer worldwide and the fourth most frequent cause of death having an oncological origin. It has been found that transcription factors (TF) dysregulation, leading to the significant expression modifications of genes, is a widely distributed phenomenon regarding human malignant neoplasias. These changes are key determinants regarding tumour’s behaviour as they contribute to cell differentiation/proliferation, migration and metastasis, as well as resistance to chemotherapeutic agents. The forkhead box (FOX) transcription factor family consists of an evolutionarily conserved group of transcriptional regulators engaged in numerous functions during development and adult life. Their dysfunction has been associated with human diseases. Several FOX gene subgroup transcriptional disturbances, affecting numerous complex molecular cascades, have been linked to a wide range of cancer types highlighting their potential usefulness as molecular biomarkers. At least 14 FOX subgroups have been related to CRC pathogenesis, thereby underlining their role for diagnosis, prognosis and treatment purposes. This manuscript aims to provide, for the first time, a comprehensive review of FOX genes’ roles during CRC pathogenesis. The molecular and functional characteristics of most relevant FOX molecules (FOXO, FOXM1, FOXP3) have been described within the context of CRC biology, including their usefulness regarding diagnosis and prognosis. Potential CRC therapeutics (including genome-editing approaches) involving FOX regulation have also been included. Taken together, the information provided here should enable a better understanding of FOX genes’ function in CRC pathogenesis for basic science researchers and clinicians.
    [Show full text]
  • FOXQ1 Controls the Induced Differentiation of Melanocytic Cells
    Cell Death & Differentiation (2018) 25:1040–1049 https://doi.org/10.1038/s41418-018-0066-y ARTICLE FOXQ1 controls the induced differentiation of melanocytic cells 1,7 1 1 1 1 Archis Bagati ● Anna Bianchi-Smiraglia ● Sudha Moparthy ● Kateryna Kolesnikova ● Emily E. Fink ● 1 1 1 1 1 1 Masha Kolesnikova ● Matthew V. Roll ● Peter Jowdy ● David W. Wolff ● Anthony Polechetti ● Dong Hyun Yun ● 1 1 1 1 1 Brittany C. Lipchick ● Leslie M. Paul ● Brian Wrazen ● Kalyana Moparthy ● Shaila Mudambi ● 2 3 4 1 4 1 Galina E. Morozevich ● Sofia G. Georgieva ● Jianmin Wang ● Gal Shafirstein ● Song Liu ● Eugene S. Kandel ● 2 5 1,6 1 Albert E. Berman ● Neil F. Box ● Gyorgy Paragh ● Mikhail A. Nikiforov Received: 9 October 2017 / Revised: 26 December 2017 / Accepted: 11 January 2018 / Published online: 20 February 2018 © ADMC Associazione Differenziamento e Morte Cellulare 2018 Abstract Oncogenic transcription factor FOXQ1 has been implicated in promotion of multiple transformed phenotypes in carcinoma cells. Recently, we have characterized FOXQ1 as a melanoma tumor suppressor that acts via repression of N-cadherin gene, and invasion and metastasis. Here we report that FOXQ1 induces differentiation in normal and transformed melanocytic cells at least partially via direct transcriptional activation of MITF gene, melanocytic lineage-specific regulator of differentiation. Importantly, we demonstrate that pigmentation induced in cultured melanocytic cells and in mice by 1234567890();,: activation of cAMP/CREB1 pathway depends in large part on FOXQ1. Moreover, our data reveal that FOXQ1 acts as a critical mediator of BRAFV600E-dependent regulation of MITF levels, thus providing a novel link between two major signal transduction pathways controlling MITF and differentiation in melanocytic cells.
    [Show full text]
  • CAR-Null, Cyp3a-Null, and Cyp2b9/10/13-Null Mice
    UC Berkeley UC Berkeley Previously Published Works Title Compensatory changes in CYP expression in three different toxicology mouse models: CAR- null, Cyp3a-null, and Cyp2b9/10/13-null mice. Permalink https://escholarship.org/uc/item/2h40v9s9 Journal PloS one, 12(3) ISSN 1932-6203 Authors Kumar, Ramiya Mota, Linda C Litoff, Elizabeth J et al. Publication Date 2017 DOI 10.1371/journal.pone.0174355 Peer reviewed eScholarship.org Powered by the California Digital Library University of California RESEARCH ARTICLE Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice Ramiya Kumar1, Linda C. Mota2, Elizabeth J. Litoff1, John P. Rooney3, W. Tyler Boswell1, Elliott Courter1, Charles M. Henderson1, Juan P. Hernandez4, J. Christopher Corton3, David D. Moore4, William S. Baldwin1,2* a1111111111 a1111111111 1 Biological Sciences, Clemson University, Clemson, SC, United States of America, 2 Environmental Toxicology, Clemson University, Pendleton, SC, United States of America, 3 NHEERL, US-EPA, Research a1111111111 Triangle Park, NC, United States of America, 4 Molecular and Cellular Biology, Baylor College of Medicine, a1111111111 Houston, TX, United States of America a1111111111 * [email protected] Abstract OPEN ACCESS Citation: Kumar R, Mota LC, Litoff EJ, Rooney JP, Targeted mutant models are common in mechanistic toxicology experiments investigating Boswell WT, Courter E, et al. (2017) Compensatory the absorption, metabolism, distribution, or elimination (ADME) of chemicals from individu- changes in CYP expression in three different als. Key models include those for xenosensing transcription factors and cytochrome P450s toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9/10/13-null mice.
    [Show full text]
  • FOXQ1 Is Overexpressed in Laryngeal Carcinoma and Affects Cell Growth, Cell Cycle Progression and Cell Invasion
    ONCOLOGY LETTERS 10: 2499-2504, 2015 FOXQ1 is overexpressed in laryngeal carcinoma and affects cell growth, cell cycle progression and cell invasion JIE ZHANG1, WEI LI1, SONG DAI2, XUHUI TAI2, JIANPING JIA2 and XING GUO1 1Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001; 2Department of Otolaryngology, The 463 Hospital of PLA, Shenyang, Liaoning 110007, P.R. China Received September 8, 2014; Accepted June 11, 2015 DOI: 10.3892/ol.2015.3530 Abstract. Forkhead box Q1 (FOXQ1) is a forkhead transcrip- the country's Northeast region (4). Significant predisposing tion factor that is involved in numerous biological processes and factors to the development and progression of LSCC, include has been shown to participate in tumorigenesis. However, the alcohol abuse and tobacco (5). Early stage LSCC may be clinical significance of the expression of this protein in laryn- effectively treated with surgery or radiotherapy (6). When geal carcinoma, and the mechanisms underlying its regulation diagnosed at an advanced stage, this disease usually requires in this disease remain unclear. The aim of present study was a combination of treatment modalities. However, although to measure the expression of FOXQ1 in laryngeal carcinoma, such combined therapy has improved local control and and to examine its effect on tumorigenesis. In the present study, overall quality of life, the local recurrence rate varies from reverse transcription‑quantitative polymerase chain reaction and 10-50%, depending on tumor stage and the overall survival western blotting were employed to measure FOXQ1 expression rate has not improved significantly over two decades (7,8). in laryngeal carcinoma tissue samples, small interfering RNA Therefore, it is necessary to identify novel biomarkers for specific to FOXQ1, was transfected into Hep2 cells and its effect use in the diagnosis of LSCC.
    [Show full text]
  • Pdgfra and B Play Critical Roles in Mediating Foxq1-Driven Breast Cancer Stemness and Chemoresistance Fanyan Meng1,2, Cecilia L
    Cancer Therapeutics, Targets, and Chemical Biology Research PDGFRa and b Play Critical Roles in Mediating Foxq1-Driven Breast Cancer Stemness and Chemoresistance Fanyan Meng1,2, Cecilia L. Speyer3, Bin Zhang4, Yongzhong Zhao4, Wei Chen1,5, David H. Gorski3, Fred R. Miller1,2, and Guojun Wu1,2 Abstract Many epithelial–mesenchymal transition (EMT)–promoting b results in more significant effects on reversing Foxq1-promoted transcription factors have been implicated in tumorigenesis and oncogenesis in vitro and in vivo than knockdown of either PDGFRa metastasis as well as chemoresistance of cancer. However, the or b alone. In addition, PDGFRb is a more potent mediator of underlying mechanisms mediating these processes are unclear. Foxq1-promoted stemness traits than PDGFRa. Finally, pharma- Here, we report that Foxq1, a forkhead box-containing transcrip- cologic inhibition or gene silencing of PDGFRs sensitizes mam- tion factor and EMT-inducing gene, promotes stemness traits and mary epithelial cells to chemotherapeutic agents in vitro and chemoresistance in mammary epithelial cells. Using an expres- in vivo. These findings collectively implicate PDGFRs as critical sion profiling assay, we identified Twist1, Zeb2, and PDGFRa and mediators of breast cancer oncogenesis and chemoresistance b as Foxq1 downstream targets. We further show that PDGFRa driven by Foxq1, with potential implications for developing novel and b can be directly regulated by Foxq1 or indirectly regulated therapeutic combinations to treat breast cancer. Cancer Res; 75(3); through the Foxq1/Twist1 axis. Knockdown of both PDGFRa and 584–93. Ó2014 AACR. Introduction remains undetermined whether there is a common mechanistic element linking these processes. Cancer recurrence, metastasis, and chemoresistance correlate Recently, epithelial–mesenchymal transition (EMT) has been with each other and contribute greatly to the mortality of patients recognized as a mechanism for breast cancer cells to acquire with breast cancer (1–3).
    [Show full text]
  • Novel Mechanistic Targets of Forkhead Box Q1 Transcription Factor in Human Breast Cancer Cells
    bioRxiv preprint doi: https://doi.org/10.1101/2020.05.26.117176; this version posted May 29, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Novel mechanistic targets of Forkhead box Q1 transcription factor in human breast cancer cells Su-Hyeong Kim*,1, Eun-Ryeong Hahm*,1, Krishna B. Singh*, and Shivendra V. Singh*,¶,2 From the *Department of Pharmacology & Chemical Biology, and ¶UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Running Title: Role of FoxQ1 in breast cancer 2To whom correspondence should be addressed: 2.32A Hillman Cancer Center Research Pavilion, UPMC Hillman Cancer Center, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-3263; Fax: 412-623-7828; E-mail: [email protected] Keywords: Breast Cancer, FoxQ1, Cell Cycle, Interleukin-1α, Interleukin-8 The transcription factor forkhead box Q1 analysis. FoxQ1 overexpression resulted (FoxQ1), which is overexpressed in in downregulation of genes associated different solid tumors, has emerged as a with cell cycle checkpoints, M phase, and key player in the pathogenesis of breast cellular response to stress/external stimuli cancer by regulating epithelial- as evidenced from the Reactome pathway mesenchymal transition, maintenance of analysis. Consequently, FoxQ1 cancer-stem like cells, and metastasis. overexpression resulted in S, G2M and However, the mechanism underlying mitotic arrest in basal-like SUM159 and oncogenic function of FoxQ1 is still not HMLE cells, but not in luminal-type fully understood. In this study, we MCF-7 cells. There were differences in compared the RNA-seq data from FoxQ1 expression of cell cycle-associated overexpressing SUM159 cells with that of proteins between FoxQ1 overexpressing empty vector-transfected control (EV) SUM159 and MCF-7 cells.
    [Show full text]
  • Epigenetic Mechanisms Are Involved in the Oncogenic Properties of ZNF518B in Colorectal Cancer
    Epigenetic mechanisms are involved in the oncogenic properties of ZNF518B in colorectal cancer Francisco Gimeno-Valiente, Ángela L. Riffo-Campos, Luis Torres, Noelia Tarazona, Valentina Gambardella, Andrés Cervantes, Gerardo López-Rodas, Luis Franco and Josefa Castillo SUPPLEMENTARY METHODS 1. Selection of genomic sequences for ChIP analysis To select the sequences for ChIP analysis in the five putative target genes, namely, PADI3, ZDHHC2, RGS4, EFNA5 and KAT2B, the genomic region corresponding to the gene was downloaded from Ensembl. Then, zoom was applied to see in detail the promoter, enhancers and regulatory sequences. The details for HCT116 cells were then recovered and the target sequences for factor binding examined. Obviously, there are not data for ZNF518B, but special attention was paid to the target sequences of other zinc-finger containing factors. Finally, the regions that may putatively bind ZNF518B were selected and primers defining amplicons spanning such sequences were searched out. Supplementary Figure S3 gives the location of the amplicons used in each gene. 2. Obtaining the raw data and generating the BAM files for in silico analysis of the effects of EHMT2 and EZH2 silencing The data of siEZH2 (SRR6384524), siG9a (SRR6384526) and siNon-target (SRR6384521) in HCT116 cell line, were downloaded from SRA (Bioproject PRJNA422822, https://www.ncbi. nlm.nih.gov/bioproject/), using SRA-tolkit (https://ncbi.github.io/sra-tools/). All data correspond to RNAseq single end. doBasics = TRUE doAll = FALSE $ fastq-dump -I --split-files SRR6384524 Data quality was checked using the software fastqc (https://www.bioinformatics.babraham. ac.uk /projects/fastqc/). The first low quality removing nucleotides were removed using FASTX- Toolkit (http://hannonlab.cshl.edu/fastxtoolkit/).
    [Show full text]
  • Engineered Type 1 Regulatory T Cells Designed for Clinical Use Kill Primary
    ARTICLE Acute Myeloid Leukemia Engineered type 1 regulatory T cells designed Ferrata Storti Foundation for clinical use kill primary pediatric acute myeloid leukemia cells Brandon Cieniewicz,1* Molly Javier Uyeda,1,2* Ping (Pauline) Chen,1 Ece Canan Sayitoglu,1 Jeffrey Mao-Hwa Liu,1 Grazia Andolfi,3 Katharine Greenthal,1 Alice Bertaina,1,4 Silvia Gregori,3 Rosa Bacchetta,1,4 Norman James Lacayo,1 Alma-Martina Cepika1,4# and Maria Grazia Roncarolo1,2,4# Haematologica 2021 Volume 106(10):2588-2597 1Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 2Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford School of Medicine, Stanford, CA, USA; 3San Raffaele Telethon Institute for Gene Therapy, Milan, Italy and 4Center for Definitive and Curative Medicine, Stanford School of Medicine, Stanford, CA, USA *BC and MJU contributed equally as co-first authors #AMC and MGR contributed equally as co-senior authors ABSTRACT ype 1 regulatory (Tr1) T cells induced by enforced expression of interleukin-10 (LV-10) are being developed as a novel treatment for Tchemotherapy-resistant myeloid leukemias. In vivo, LV-10 cells do not cause graft-versus-host disease while mediating graft-versus-leukemia effect against adult acute myeloid leukemia (AML). Since pediatric AML (pAML) and adult AML are different on a genetic and epigenetic level, we investigate herein whether LV-10 cells also efficiently kill pAML cells. We show that the majority of primary pAML are killed by LV-10 cells, with different levels of sensitivity to killing. Transcriptionally, pAML sensitive to LV-10 killing expressed a myeloid maturation signature.
    [Show full text]
  • TFAP2 Transcription Factors Are Regulators of Lipid Droplet Biogenesis
    bioRxiv preprint doi: https://doi.org/10.1101/282376; this version posted March 14, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 TFAP2 transcription factors are 2 regulators of lipid droplet biogenesis 3 4 5 Cameron C Scott1, Stefania Vossio1, Jacques Rougemont2, Jean Gruenberg1,3 6 7 8 9 10 11 12 1. Department of Biochemistry, University of Geneva, 30 quai Ernest Ansermet 13 1211 Geneva 4, Switzerland 14 2. Department of Theoretical Physics, University of Geneva, 24 quai Ernest Ansermet 15 1211 Geneva 4, Switzerland 16 17 3. To whom correspondence should be addressed: [email protected] 18 19 20 21 22 1 bioRxiv preprint doi: https://doi.org/10.1101/282376; this version posted March 14, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Abstract 2 How trafficking pathways and organelle abundance adapt in response to metabolic 3 and physiological changes is still mysterious, although a few transcriptional regulators of 4 organellar biogenesis have been identified in recent years. We previously found that the Wnt 5 signaling directly controls lipid droplet formation, linking the cell storage capacity to the 6 established functions of Wnt in development and differentiation. In the present paper, we 7 report that Wnt-induced lipid droplet biogenesis does not depend on the canonical TCF/LEF 8 transcription factors.
    [Show full text]
  • Discerning the Role of Foxa1 in Mammary Gland
    DISCERNING THE ROLE OF FOXA1 IN MAMMARY GLAND DEVELOPMENT AND BREAST CANCER by GINA MARIE BERNARDO Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy Dissertation Adviser: Dr. Ruth A. Keri Department of Pharmacology CASE WESTERN RESERVE UNIVERSITY January, 2012 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Gina M. Bernardo ______________________________________________________ Ph.D. candidate for the ________________________________degree *. Monica Montano, Ph.D. (signed)_______________________________________________ (chair of the committee) Richard Hanson, Ph.D. ________________________________________________ Mark Jackson, Ph.D. ________________________________________________ Noa Noy, Ph.D. ________________________________________________ Ruth Keri, Ph.D. ________________________________________________ ________________________________________________ July 29, 2011 (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. DEDICATION To my parents, I will forever be indebted. iii TABLE OF CONTENTS Signature Page ii Dedication iii Table of Contents iv List of Tables vii List of Figures ix Acknowledgements xi List of Abbreviations xiii Abstract 1 Chapter 1 Introduction 3 1.1 The FOXA family of transcription factors 3 1.2 The nuclear receptor superfamily 6 1.2.1 The androgen receptor 1.2.2 The estrogen receptor 1.3 FOXA1 in development 13 1.3.1 Pancreas and Kidney
    [Show full text]
  • Transcriptomic Profiles of Aging in Naïve and Memory CD4+ Cells From
    Taylor et al. Immunity & Ageing (2017) 14:15 DOI 10.1186/s12979-017-0092-5 RESEARCH Open Access Transcriptomic profiles of aging in naïve and memory CD4+ cells from mice Jackson Taylor1,2,3*, Lindsay Reynolds1, Li Hou1, Kurt Lohman1, Wei Cui1, Stephen Kritchevsky2, Charles McCall2 and Yongmei Liu1 Abstract Background: CD4+ T cells can be broadly divided into naïve and memory subsets, each of which are differentially impaired by the aging process. It is unclear if and how these differences are reflected at the transcriptomic level. We performed microarray profiling on RNA derived from naïve (CD44low) and memory (CD44high) CD4+ T cells derived from young (2–3 month) and old (28 month) mice, in order to better understand the mechanisms of age-related functional alterations in both subsets. We also performed follow-up bioinformatic analyses in order to determine the functional consequences of gene expression changes in both of these subsets, and identify regulatory factors potentially responsible for these changes. Results: We found 185 and 328 genes differentially expressed (FDR ≤ 0.05) in young vs. old naïve and memory cells, respectively, with 50 genes differentially expressed in both subsets. Functional annotation analyses highlighted an increase in genes involved in apoptosis specific to aged naïve cells. Both subsets shared age-related increases in inflammatory signaling genes, along with a decrease in oxidative phosphorylation genes. Cis-regulatory analyses revealed enrichment of multiple transcription factor binding sites near genes with age-associated expression, in particular NF-κB and several forkhead box transcription factors. Enhancer associated histone modifications were enriched near genes down-regulated in naïve cells.
    [Show full text]