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https://www.readbyqxmd.com/read/28985527/evolutionarily-distinctive-transcriptional-and-signaling-programs-drive-human-germ-cell-lineage-specification-from-pluripotent-stem-cells
#1
Yoji Kojima, Kotaro Sasaki, Shihori Yokobayashi, Yoshitake Sakai, Tomonori Nakamura, Yukihiro Yabuta, Fumio Nakaki, So Nagaoka, Knut Woltjen, Akitsu Hotta, Takuya Yamamoto, Mitinori Saitou
Germline specification underlies human reproduction and evolution, but it has proven difficult to study in humans since it occurs shortly after blastocyst implantation. This process can be modeled with human induced pluripotent stem cells (hiPSCs) by differentiating them into primordial germ cell-like cells (hPGCLCs) through an incipient mesoderm-like cell (iMeLC) state. Here, we elucidate the key transcription factors and their interactions with important signaling pathways in driving hPGCLC differentiation from iPSCs...
October 5, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/28981894/principles-for-the-regulation-of-multiple-developmental-pathways-by-a-versatile-transcriptional-factor-blimp1
#2
Tadahiro Mitani, Yukihiro Yabuta, Hiroshi Ohta, Tomonori Nakamura, Chika Yamashiro, Takuya Yamamoto, Mitinori Saitou, Kazuki Kurimoto
Single transcription factors (TFs) regulate multiple developmental pathways, but the underlying mechanisms remain unclear. Here, we quantitatively characterized the genome-wide occupancy profiles of BLIMP1, a key transcriptional regulator for diverse developmental processes, during the development of three germ-layer derivatives (photoreceptor precursors, embryonic intestinal epithelium and plasmablasts) and the germ cell lineage (primordial germ cells). We identified BLIMP1-binding sites shared among multiple developmental processes, and such sites were highly occupied by BLIMP1 with a stringent recognition motif and were located predominantly in promoter proximities...
September 11, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28969006/the-molecular-characterization-of-porcine-egg-precursor-cells
#3
Te-Sha Tsai, Jacqueline Johnson, Yvonne White, Justin C John
Female-factor infertility can be caused by poor oocyte quality and depleted ovarian reserves. Egg precursor cells (EPCs), isolated from the ovarian cortex, have the potential to be used to overcome female infertility. We aimed to define the origins of EPCs by analyzing their gene expression profiles and mtDNA content using a mini-pig model. We characterized FAC-sorted DDX4(+)-derived porcine EPCs by performing RNA-sequencing and determined that they utilize pathways important for cell cycle and proliferation, which supports the existence of adult mitotically active oogonial cells...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28955330/perturbation-of-b-cell-gene-expression-persists-in-hiv-infected-children-despite-effective-antiretroviral-therapy-and-predicts-h1n1-response
#4
Nicola Cotugno, Lesley De Armas, Suresh Pallikkuth, Stefano Rinaldi, Biju Issac, Alberto Cagigi, Paolo Rossi, Paolo Palma, Savita Pahwa
Despite effective antiretroviral therapy (ART), HIV-infected individuals with apparently similar clinical and immunological characteristics can vary in responsiveness to vaccinations. However, molecular mechanisms responsible for such impairment, as well as biomarkers able to predict vaccine responsiveness in HIV-infected children, remain unknown. Following the hypothesis that a B cell qualitative impairment persists in HIV-infected children (HIV) despite effective ART and phenotypic B cell immune reconstitution, the aim of the current study was to investigate B cell gene expression of HIV compared to age-matched healthy controls (HCs) and to determine whether distinct gene expression patterns could predict the ability to respond to influenza vaccine...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28935958/differential-regulation-of-effector-and-regulatory-t-cell-function-by-blimp1
#5
Rashmi Bankoti, Chihiro Ogawa, Truc Nguyen, Lena Emadi, Michael Couse, Soofia Salehi, Xuemo Fan, Deepti Dhall, Yizhou Wang, Jordan Brown, Vincent Funari, Jie Tang, Gislâine A Martins
The transcriptional regulator Blimp1 plays crucial roles in controlling terminal differentiation in several lineages. In T cells, Blimp1 is expressed in both effector (Teff) and regulatory (Treg) cells, and mice with T cell-specific deletion of Blimp1 (Blimp1CKO mice) spontaneously develop severe intestinal inflammation, indicating a crucial role for Blimp1 in T cell homeostasis regulation. Blimp1 has been shown to function as a direct activator of the Il10 gene and although its requirement for IL10 expression has been demonstrated in both Treg and Teff cells under inflammatory conditions, the intrinsic requirement of Blimp1 for homeostatic maintenance of these T cell subsets had not been investigated...
September 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28878266/transglutaminase-2-regulates-osteoclast-differentiation-via-a-blimp1-dependent-pathway
#6
Woo-Shin Kim, Haemin Kim, Eui Man Jeong, Hyung Joon Kim, Zang Hee Lee, In-Gyu Kim, Hong-Hee Kim
Transglutaminase 2 (TG2) performs multiple reactions, including transamidation, and also plays a role in signal transduction as a GTP-binding protein. In this study, we reveal that TG2 controls osteoclast differentiation and bone homeostasis in mice. Osteoclasts specifically expressed the TG2 isoform among eight TG family members. Suppression in TG2 expression with siRNA led to increased osteoclast formation from primary mouse precursor cells in response to receptor activator of nuclear factor kappaB ligand (RANKL)...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28875978/il4-and-il21-cooperate-to-induce-the-high-bcl6-protein-level-required-for-germinal-center-formation
#7
Stéphane Chevrier, Tobias Kratina, Dianne Emslie, David M Tarlinton, Lynn M Corcoran
Bcl6 is a transcriptional repressor and critical mediator of the germinal center reaction during a T cell dependent antibody response, where it enables somatic hypermutation of immunoglobulin genes and inhibits terminal differentiation via repression of Blimp1. It can also contribute to the development of diffuse large B cell lymphoma when expressed inappropriately. Bcl6 regulation is mediated both at the transcriptional and post-transcriptional levels, and in particular a strong signal through the B cell receptor causes rapid proteasomal degradation of Bcl6...
September 6, 2017: Immunology and Cell Biology
https://www.readbyqxmd.com/read/28851699/an-aberrant-notch2-bcr-signaling-axis-in-b-cells-from-patients-with-chronic-gvhd
#8
Jonathan C Poe, Wei Jia, Hsuan Su, Sarah Anand, Jeremy J Rose, Prasanthi V Tata, Amy N Suthers, Corbin D Jones, Pei Fen Kuan, Benjamin G Vincent, Jonathan S Serody, Mitchell E Horwitz, Vincent T Ho, Steven Z Pavletic, Frances T Hakim, Kouros Owzar, Dadong Zhang, Bruce R Blazar, Christian W Siebel, Nelson J Chao, Ivan Maillard, Stefanie Sarantopoulos
B Cell Receptor (BCR)-activated B cells contribute to pathogenesis in chronic graft-versus-host disease (cGVHD), a condition manifested by both B cell autoreactivity and immune deficiency. We hypothesized that constitutive BCR activation precluded functional B cell maturation in cGVHD. To address this, we examined BCR-NOTCH2 synergy, since Notch has been shown to increase BCR responsiveness in normal mouse B cells. We conducted ex vivo activation and signaling assays of 30 primary samples from HCT patients with and without cGVHD...
August 29, 2017: Blood
https://www.readbyqxmd.com/read/28835384/ezh2-inhibition-by-tazemetostat-results-in-altered-dependency-on-b-cell-activation-signaling%C3%A2-in-dlbcl
#9
Dorothy Brach, Danielle Johnston-Blackwell, Allison Drew, Trupti Lingaraj, Vinny Motwani, Natalie M Warholic, Igor Feldman, Christopher Plescia, Jesse J Smith, Robert A Copeland, Heike Keilhack, Elayne Chan-Penebre, Sarah K Knutson, Scott A Ribich, Alejandra Raimondi, Michael J Thomenius
The EZH2 small molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin's Lymphoma (NHL).  We have previously shown that EZH2 inhibitors display an anti-proliferative effect in multiple pre-clinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2 Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model...
August 23, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28833081/transcriptional-repressor-blimp1-regulates-follicular-regulatory-t-cells-homeostasis-and-function
#10
Guang Yang, Xiaosu Yang, Junmei Zhang, Guancheng Li, Dandan Zheng, Anjiao Peng, Jue Hu, Liqun Xu, Baifeng Yang, Huan Yang, Wenbin Zhou, Erdem Tuzun, Jing Li
The B lymphocyte-induced maturation protein 1(Blimp1) regulates T cell homeostasis and function. Loss of Blimp1 could double the proportion of TFR cells. However, the effects that Blimp1 may have on the function of TFR cells remain unknown. Here we document the function for Blimp1 in TFR cells in vitro and in vivo. Data presented in this study demonstrated that TFR cells indirectly inhibit the activation and differentiation of B cells by negatively regulating TFH cells, thus lowering the secretion of antibody...
August 20, 2017: Immunology
https://www.readbyqxmd.com/read/28829770/combinatorial-regulation-of-a-blimp1-prdm1-enhancer-in-the-mouse-retina
#11
Taylor S Mills, Tatiana Eliseeva, Stephanie M Bersie, Grace Randazzo, Jhenya Nahreini, Ko Uoon Park, Joseph A Brzezinski
The mouse retina comprises seven major cell types that exist in differing proportions. They are generated from multipotent progenitors in a stochastic manner, such that the relative frequency of any given type generated changes over time. The mechanisms determining the proportions of each cell type are only partially understood. Photoreceptors and bipolar interneurons are derived from cells that express Otx2. Within this population, Blimp1 (Prdm1) helps set the balance between photoreceptors and bipolar cells by suppressing bipolar identity in most of the cells...
2017: PloS One
https://www.readbyqxmd.com/read/28790031/blimp1-induces-transient-metastatic-heterogeneity-in-pancreatic-cancer
#12
Shin-Heng Chiou, Viviana I Risca, Gordon X Wang, Dian Yang, Barbara M Grüner, Arwa S Kathiria, Rosanna K Ma, Dedeepya Vaka, Pauline Chu, Margaret Kozak, Laura Castellini, Edward E Graves, Grace E Kim, Philippe Mourrain, Albert C Koong, Amato J Giaccia, Monte M Winslow
Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic and deadly cancers. Despite the clinical significance of metastatic spread, our understanding of molecular mechanisms that drive PDAC metastatic ability remains limited. By generating a genetically engineered mouse model of human PDAC, we uncover a transient subpopulation of cancer cells with exceptionally high metastatic ability. Global gene expression profiling and functional analyses uncovered the transcription factor BLIMP1 as a driver of PDAC metastasis...
October 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28768724/pd-l2-regulates-b-1-cell-antibody-production-against-phosphorylcholine-through-an-il-5-dependent-mechanism
#13
Jerome T McKay, Marcela A Haro, Christina A Daly, Rama D Yammani, Bing Pang, W Edward Swords, Karen M Haas
B-1 cells produce natural Abs which provide an integral first line of defense against pathogens while also performing important homeostatic housekeeping functions. In this study, we demonstrate that programmed cell death 1 ligand 2 (PD-L2) regulates the production of natural Abs against phosphorylcholine (PC). Naive PD-L2-deficient (PD-L2(-/-)) mice produced significantly more PC-reactive IgM and IgA. This afforded PD-L2(-/-) mice with selectively enhanced protection against PC-expressing nontypeable Haemophilus influenzae, but not PC-negative nontypeable Haemophilus influenzae, relative to wild-type mice...
September 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28758191/interleukin-27-signalling-induces-stem-cell-antigen-1-expression-in-t-lymphocytes-in%C3%A2-vivo
#14
Zhihao Liu, Lisha Wu, Jing Zhu, Xiaotong Zhu, Jianmin Zhu, Jin-Qing Liu, Jianchao Zhang, Jonathan P Davis, Sanjay Varikuti, Abhay R Satoskar, Jie Zhou, Ming-Song Li, Xue-Feng Bai
Stem cell antigen-1 (Sca-1/Ly6A/E) is a cell surface glycoprotein that is often used as a biomarker for stem cells and cell stemness. However, it is not clear what factors can directly induce the expression of Sca-1/Ly6A/E in T lymphocytes in vivo, and if induction of Sca-1 is associated with T cell stemness. In this study, we show that interleukin-27 (IL-27), a member of the IL-12 family of cytokines, directly induces Sca-1 expression in T cells in vivo. We found that mice-deficient for IL-27 (either P28 or EBI3) or its signalling (IL-27Rα) had profound reduction of Sca-1 expression in naive (CD62L(+)  CD44(-) ), memory (CD62L(+)  CD44(+) ) and effector (CD62L(-)  CD44(+) ) T cells...
July 31, 2017: Immunology
https://www.readbyqxmd.com/read/28757909/metabolic-reprogramming-autophagy-and-reactive-oxygen-species-are-necessary-for-primordial-germ-cell-reprogramming-into-pluripotency
#15
D Sainz de la Maza, A Moratilla, V Aparicio, C Lorca, Y Alcaina, D Martín, M P De Miguel
Cellular reprogramming is accompanied by a metabolic shift from oxidative phosphorylation (OXPHOS) toward glycolysis. Previous results from our laboratory showed that hypoxia alone is able to reprogram primordial germ cells (PGCs) into pluripotency and that this action is mediated by hypoxia-inducible factor 1 (HIF1). As HIF1 exerts a myriad of actions by upregulating several hundred genes, to ascertain whether the metabolic switch toward glycolysis is solely responsible for reprogramming, PGCs were cultured in the presence of a pyruvate kinase M2 isoform (PKM2) activator, or glycolysis was promoted by manipulating PPARγ...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28754907/mapping-the-chromatin-landscape-and-blimp1-transcriptional-targets-that-regulate-trophoblast-differentiation
#16
Andrew C Nelson, Arne W Mould, Elizabeth K Bikoff, Elizabeth J Robertson
Trophoblast stem cells (TSCs) give rise to specialized cell types within the placenta. However, the regulatory mechanisms that guide trophoblast cell fate decisions during placenta development remain ill defined. Here we exploited ATAC-seq and transcriptional profiling strategies to describe dynamic changes in gene expression and chromatin accessibility during TSC differentiation. We detect significantly increased chromatin accessibility at key genes upregulated as TSCs exit from the stem cell state. However, downregulated gene expression is not simply due to the loss of chromatin accessibility in proximal regions...
July 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28723546/local-modulation-of-antigen-presenting-cell-development-after-resolution-of-pneumonia-induces-long-term-susceptibility-to-secondary-infections
#17
Antoine Roquilly, Hamish E G McWilliam, Cedric Jacqueline, Zehua Tian, Raphael Cinotti, Marie Rimbert, Linda Wakim, Irina Caminschi, Mireille H Lahoud, Gabrielle T Belz, Axel Kallies, Justine D Mintern, Karim Asehnoune, Jose A Villadangos
Lung infections cause prolonged immune alterations and elevated susceptibility to secondary pneumonia. We found that, after resolution of primary viral or bacterial pneumonia, dendritic cells (DC), and macrophages exhibited poor antigen-presentation capacity and secretion of immunogenic cytokines. Development of these "paralyzed" DCs and macrophages depended on the immunosuppressive microenvironment established upon resolution of primary infection, which involved regulatory T (Treg) cells and the cytokine TGF-β...
July 18, 2017: Immunity
https://www.readbyqxmd.com/read/28711945/the-molecular-characterization-of-porcine-egg-precursor-cells
#18
Te-Sha Tsai, Jacqueline Johnson, Yvonne White, Justin C St John
Female-factor infertility can be caused by poor oocyte quality and depleted ovarian reserves. Egg precursor cells (EPCs), isolated from the ovarian cortex, have the potential to be used to overcome female infertility. We aimed to define the origins of EPCs by analyzing their gene expression profiles and mtDNA content using a mini-pig model. We characterized FAC-sorted DDX4+-derived porcine EPCs by performing RNA-sequencing and determined that they utilize pathways important for cell cycle and proliferation, which supports the existence of adult mitotically active oogonial cells...
June 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28701508/prdm1-regulates-thymic-epithelial-function-to-prevent-autoimmunity
#19
Natalie A Roberts, Brian D Adams, Nicholas I McCarthy, Reuben M Tooze, Sonia M Parnell, Graham Anderson, Susan M Kaech, Valerie Horsley
Autoimmunity is largely prevented by medullary thymic epithelial cells (TECs) through their expression and presentation of tissue-specific Ags to developing thymocytes, resulting in deletion of self-reactive T cells and supporting regulatory T cell development. The transcription factor Prdm1 has been implicated in autoimmune diseases in humans through genome-wide association studies and in mice using cell type-specific deletion of Prdm1 in T and dendritic cells. In this article, we demonstrate that Prdm1 functions in TECs to prevent autoimmunity in mice...
August 15, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28668474/dermal-blimp1-acts-downstream-of-epidermal-tgf%C3%AE-and-wnt-%C3%AE-catenin-to%C3%A2-regulate-hair-follicle-formation-and%C3%A2-growth
#20
Stephanie B Telerman, Emanuel Rognoni, Inês Sequeira, Angela Oliveira Pisco, Beate M Lichtenberger, Oliver J Culley, Priyalakshmi Viswanathan, Ryan R Driskell, Fiona M Watt
B-lymphocyte-induced maturation protein 1 (Blimp1) is a transcriptional repressor that regulates cell growth and differentiation in multiple tissues, including skin. Although in the epidermis Blimp1 is important for keratinocyte and sebocyte differentiation, its role in dermal fibroblasts is unclear. Here we show that Blimp1 is dynamically regulated in dermal papilla cells during hair follicle (HF) morphogenesis and the postnatal hair cycle, preceding dermal Wnt/β-catenin activation. Blimp1 ablation in E12...
June 28, 2017: Journal of Investigative Dermatology
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