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Difeng Fang, Kairong Cui, Gangqing Hu, Rama Krishna Gurram, Chao Zhong, Andrew J Oler, Ryoji Yagi, Ming Zhao, Suveena Sharma, Pentao Liu, Bing Sun, Keji Zhao, Jinfang Zhu
GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we show that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein-protein interaction, and they colocalize at many important cis-regulatory elements in Th2 cells...
March 7, 2018: Journal of Experimental Medicine
Daniel H Miller, Dexter X Jin, Ethan S Sokol, Janel R Cabrera, Daphne A Superville, Rebecca A Gorelov, Charlotte Kuperwasser, Piyush B Gupta
The epithelial compartment of the mammary gland contains basal and luminal cell lineages, as well as stem and progenitor cells that reside upstream in the differentiation hierarchy. Stem and progenitor cell differentiation is regulated to maintain adult tissue and mediate expansion during pregnancy and lactation. The genetic factors that regulate the transition of cells between differentiation states remain incompletely understood. Here, we present a genome-scale method to discover genes driving cell-state specification...
February 22, 2018: Stem Cell Reports
Gangqing Hu, Kairong Cui, Difeng Fang, Satoshi Hirose, Xun Wang, Darawalee Wangsa, Wenfei Jin, Thomas Ried, Pentao Liu, Jinfang Zhu, Ellen V Rothenberg, Keji Zhao
How chromatin reorganization coordinates differentiation and lineage commitment from hematopoietic stem and progenitor cells (HSPCs) to mature immune cells has not been well understood. Here, we carried out an integrative analysis of chromatin accessibility, topologically associating domains, AB compartments, and gene expression from HSPCs to CD4+ CD8+ T cells. We found that abrupt genome-wide changes at all three levels of chromatin organization occur during the transition from double-negative stage 2 (DN2) to DN3, accompanying the T lineage commitment...
February 20, 2018: Immunity
Alejandro Gutierrez, Alex Kentsis
Advances in the classification of acute leukaemias have led to improved outcomes for a substantial fraction of patients. However, chemotherapy resistance remains a major problem for specific subsets of acute leukaemias. Here, we propose that a molecularly distinct subtype of acute leukaemia with shared myeloid and T cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukaemia (AMTL), is divided across 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-lymphoid lineages, such as myeloperoxidase and CD3...
February 14, 2018: British Journal of Haematology
Gang Fang, Qing Huai Zhang, Qianqian Tang, Zuling Jiang, Shasha Xing, Jianying Li, Yuzhou Pang
Rheumatoid arthritis (RA) represents a common systemic autoimmune disease which lays chronic and persistent pain on patients. The purpose of our study is to identify novel RA-related genes and biological processes/pathways. All the datasets of this study, including gene expression and DNA methylation datasets of RA and OA samples, were obtained from the free available database, i.e. Gene Expression Omnibus (GEO). We firstly identified the differentially expressed genes (DEGs) between RA and OA samples through the limma package of R programming software followed by the functional enrichment analysis in the Database for Annotation, Visualization and Integrated Discovery (DAVID) for the exploring of potential involved biological processes/pathways of DEGs...
January 9, 2018: Oncotarget
Michaela C Baldauf, Martin F Orth, Marlene Dallmayer, Aruna Marchetto, Julia S Gerke, Rebeca Alba Rubio, Merve M Kiran, Julian Musa, Maximilian M L Knott, Shunya Ohmura, Jing Li, Nusret Akpolat, Ayse N Akatli, Özlem Özen, Uta Dirksen, Wolfgang Hartmann, Enrique de Alava, Daniel Baumhoer, Giuseppina Sannino, Thomas Kirchner, Thomas G P Grünewald
Ewing sarcoma is an undifferentiated small-round-cell sarcoma. Although molecular detection of pathognomonic EWSR1-ETS fusions such as EWSR1-FLI1 enables definitive diagnosis, substantial confusion can arise if molecular diagnostics are unavailable. Diagnosis based on the conventional immunohistochemical marker CD99 is unreliable due to its abundant expression in morphological mimics. To identify novel diagnostic immunohistochemical markers for Ewing sarcoma, we performed comparative expression analyses in 768 tumors representing 21 entities including Ewing-like sarcomas, which confirmed that CIC-DUX4- , BCOR-CCNB3- , EWSR1-NFATc2- , and EWSR1-ETS -translocated sarcomas are distinct entities, and revealed that ATP1A1 , BCL11B , and GLG1 constitute specific markers for Ewing sarcoma...
January 5, 2018: Oncotarget
Chih-Yen Wang, Yuan-Ting Sun, Kuan-Min Fang, Chia-Hsin Ho, Chung-Shi Yang, Shun-Fen Tzeng
B-cell CLL/lymphoma 11B (Bcl11b) - a C2H2 zinc finger transcriptional factor - is known to regulate neuronal differentiation and function in the development of the central nervous system (CNS). Although its expression is reduced during oligodendrocyte (OLG) differentiation, its biological role in OLGs remains unknown. In this study, we found that the downregulation of Bcl11b gene expression in glial progenitor cells (GPCs) by lentivirus-mediated gene knockdown (KD) causes a reduction in cell proliferation with inhibited expression of stemness-related genes, while increasing the expression of cell cyclin regulator p21...
2018: Frontiers in Molecular Neuroscience
Noémie Gensous, Claudio Franceschi, Bonnie B Blomberg, Chiara Pirazzini, Francesco Ravaioli, Davide Gentilini, Anna Maria Di Blasio, Paolo Garagnani, Daniela Frasca, Maria Giulia Bacalini
Several evidences indicate that aging negatively affects the effectiveness of influenza vaccination. Although it is well established that immunosenescence has an important role in vaccination response, the molecular pathways underlying this process are largely unknown. Given the importance of epigenetic remodeling in aging, here we analyzed the relationship between responsiveness to influenza vaccination and DNA methylation profiles in healthy subjects of different ages. Peripheral blood mononuclear cells were collected from 44 subjects (age range: 19-90 years old) immediately before influenza vaccination...
January 19, 2018: Experimental Gerontology
Piotr Grabarczyk, Passorn Winkler, Martin Delin, Praveen K Sappa, Sander Bekeschus, Petra Hildebrandt, Grzegorz K Przybylski, Uwe Völker, Elke Hammer, Christian A Schmidt
The BCL11B gene encodes a Krüppel-like, sequence-specific zinc finger (ZF) transcription factor that acts as either a repressor or an activator, depending on its posttranslational modifications. The importance of BCL11B in numerous biological processes in multiple organs has been well established in mouse knockout models. The phenotype of the first de novo monoallelic germ line missense mutation in the BCL11B gene (encoding N441K) strongly implies that the mutant protein acts in a dominant-negative manner by neutralizing the unaffected protein through the formation of a nonfunctional dimer...
March 1, 2018: Molecular and Cellular Biology
Shinya Hatano, Tesshin Murakami, Naoto Noguchi, Hisakata Yamada, Yasunobu Yoshikai
We recently found that a unique subset of innate-like γδ T cells develops from the DN2a stage of the fetal thymus independently of the zinc-finger transcription factor B cell leukemia/lymphoma 11b (Bcl11b). Herein, we characterize these Bcl11b-independent γδ T cells in the periphery as CD5(-)NK1.1(+) and Granzyme B(+), and we show that they are capable of producing interferon (IFN)-γ upon T cell receptor stimulation without Ca(2+) influx. In wild-type mice, these cells were sparse in lymphoid tissues but abundant in non-lymphoid tissues, such as the liver...
October 31, 2017: Cell Reports
Peng Jin, Hongxi Chen, Jinliang Xie, Cheng Zhou, Xiangrong Zhu
Kidney transplantation is an effective final therapeutic procedure for patients with end-stage kidney failure. Although advanced immunosuppressive therapy is administered following transplantation, certain patients still suffer from acute allograft rejection. MicroRNAs (miRs) have a potential diagnostic and therapeutic value for acute renal allograft rejection; however, their underlying mechanism of action is largely unknown. In the present study, an increased level of miR-650 was identified to be associated with the downregulation of B-cell CLL/lymphoma 11B (BCL11B) expression in acute renal allograft rejection...
October 17, 2017: International Journal of Molecular Medicine
Laura D Mathies, Fazil Aliev, Andrew G Davies, Danielle M Dick, Jill C Bettinger
BACKGROUND: Testing for direct gene or single nucleotide polymorphism replication of association across studies may not capture the true importance of a candidate locus; rather, we suggest that relevant replication across studies may be found at the level of a biological process. We previously observed that variation in 2 members of the switching defective/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex is associated with alcohol dependence (AD) in the Irish Affected Sib Pair Study for Alcohol Dependence...
December 2017: Alcoholism, Clinical and Experimental Research
Surenchimeg Mondoon, Kensuke Shibata, Yasunobu Yoshikai
Intraepithelial lymphocytes (IELs) are resident cells localized within the intestinal epithelia and play an important role in regulating gut inflammations and host defense against pathogens. CD8α(+) TCRαβ(+) IELs are heterogeneous populations that are generated from T cell precursors including CD4(-) CD8α(-) double-negative (DN) cells and CD4(+) CD8α(+) double-positive (DP) cells. However, developmental pathways of TCRαβ(+) IELs remained unclear. To gain insight into the mechanisms, we generated mice (Bcl11b(ΔDN2) mice) that lack thymic precursors (DN CD5(+) TCRβ(+) cells) for CD4(-) CD8αα(+) TCRαβ(+) IELs...
November 2017: Immunology Letters
Satoshi Kojo, Hirokazu Tanaka, Takaho A Endo, Sawako Muroi, Ye Liu, Wooseok Seo, Mari Tenno, Kiyokazu Kakugawa, Yoshinori Naoe, Krutula Nair, Kazuyo Moro, Yoshinori Katsuragi, Akinori Kanai, Toshiya Inaba, Takeshi Egawa, Byrappa Venkatesh, Aki Minoda, Ryo Kominami, Ichiro Taniuchi
T-lineage committed precursor thymocytes are screened by a fate-determination process mediated via T cell receptor (TCR) signals for differentiation into distinct lineages. However, it remains unclear whether any antecedent event is required to couple TCR signals with the transcriptional program governing lineage decisions. Here we show that Bcl11b, known as a T-lineage commitment factor, is essential for proper expression of ThPOK and Runx3, central regulators for the CD4-helper/CD8-cytotoxic lineage choice...
September 26, 2017: Nature Communications
Yosuke Matsumoto, Hisao Nagoshi, Mihoko Yoshida, Seiichi Kato, Junya Kuroda, Kazuho Shimura, Hiroto Kaneko, Shigeo Horiike, Shigeo Nakamura, Masafumi Taniwaki
Objective It has been postulated that the normal counterpart of angioimmunoblastic T-cell lymphoma (AITL) is the follicular helper T-cell (TFH). Recent immunological studies have identified several transcription factors responsible for T-cell differentiation. The master regulators associated with T-cell, helper T-cell (Th), and TFH differentiation are reportedly BCL11B, Th-POK, and BCL6, respectively. We explored the postulated normal counterpart of AITL with respect to the expression of the master regulators of T-cell differentiation...
November 1, 2017: Internal Medicine
Takeshi Isoda, Amanda J Moore, Zhaoren He, Vivek Chandra, Masatoshi Aida, Matthew Denholtz, Jan Piet van Hamburg, Kathleen M Fisch, Aaron N Chang, Shawn P Fahl, David L Wiest, Cornelis Murre
It is now established that Bcl11b specifies T cell fate. Here, we show that in developing T cells, the Bcl11b enhancer repositioned from the lamina to the nuclear interior. Our search for factors that relocalized the Bcl11b enhancer identified a non-coding RNA named ThymoD (thymocyte differentiation factor). ThymoD-deficient mice displayed a block at the onset of T cell development and developed lymphoid malignancies. We found that ThymoD transcription promoted demethylation at CTCF bound sites and activated cohesin-dependent looping to reposition the Bcl11b enhancer from the lamina to the nuclear interior and to juxtapose the Bcl11b enhancer and promoter into a single-loop domain...
September 21, 2017: Cell
Farbod Famili, Anna-Sophia Wiekmeijer, Frank Jt Staal
T cells develop from hematopoietic stem cells in the specialized microenvironment of the thymus. The main transcriptional players of T-cell differentiation such as Notch, Tcf-1, Gata3 and Bcl11b have been identified, but their role and regulation are not yet completely understood. In humans, functional experiments on T-cell development have traditionally been rather difficult to perform, but novel in vitro culture systems and in vivo xenograft models have allowed detailed studies on human T-cell development...
August 2017: Future Science OA
Lei Zhang, Shiyun Ma, Huailiang Wang, Hang Su, Ke Su, Longjie Li
The purpose of our study was to identify new pathogenic genes used for exploring the pathogenesis of rheumatoid arthritis (RA). To screen pathogenic genes of RA, an integrated analysis was performed by using the microarray datasets in RA derived from the Gene Expression Omnibus (GEO) database. The functional annotation and potential pathways of differentially expressed genes (DEGs) were further discovered by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Afterwards, the integrated analysis of DNA methylation and gene expression profiling was used to screen crucial genes...
November 15, 2017: Gene
Davide Dulcis, Giordano Lippi, Christiana J Stark, Long H Do, Darwin K Berg, Nicholas C Spitzer
Changes in social preference of amphibian larvae result from sustained exposure to kinship odorants. To understand the molecular and cellular mechanisms of this neuroplasticity, we investigated the effects of olfactory system activation on neurotransmitter (NT) expression in accessory olfactory bulb (AOB) interneurons during development. We show that protracted exposure to kin or non-kin odorants changes the number of dopamine (DA)- or gamma aminobutyric acid (GABA)-expressing neurons, with corresponding changes in attraction/aversion behavior...
September 13, 2017: Neuron
Javier Chinen, Yousef R Badran, Raif S Geha, Janet S Chou, Ari J Fried
Advances in basic immunology in 2016 included studies that further characterized the role of different proteins in the differentiation of effector T and B cells, including cytokines and proteins involved in the actin cytoskeleton. Regulation of granule formation and secretion in cytotoxic cells was also further described by examining patients with familial hemophagocytic lymphohistiocytosis. The role of prenylation in patients with mevalonate kinase deficiency leading to inflammation has been established. We reviewed advances in clinical immunology, as well as new approaches of whole-genome sequencing and genes newly reported to be associated with immunodeficiency, such as linker of activation of T cells (LAT); B-cell CLL/lymphoma 11B (BCL11B); RGD, leucine-rich repeat, tropomodulin domain, and proline-rich domain-containing protein (RLTPR); moesin; and Janus kinase 1 (JAK1)...
October 2017: Journal of Allergy and Clinical Immunology
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