Heritability and Genetic Determinants of Normal Human Facial Shape and Body Size
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Role of Estrogen Receptor Beta and the Isoflavone Genistein
WCP2018 OR28-3 Oral session White-to-brown adipose differentiation: role of estrogen receptor beta and the isoflavone genistein Alessandra Bitto, Federica Mannino, Natasha Irrera, Giovanni Pallio, Domenica Altavilla, Francesco Squadrito Clinical and experimental medicine, University of Messina, Italy The two types of fat cells in mammals brown and white have different functions. White adipose tissue (WAT) stores excess energy in the form of triglyceride and releases free fatty acids during caloric deficiency. Brown adipose tissue (BAT) on the other hand can dissipate energy through thermogenesis. Genistein can have an effect on energy expenditure UCP (uncoupling protein) expression and protect against the obesogenic effect of a high calorie diet. The effect of genistein in inducing white-to-brown transdifferentiation was investigated in 3T3-L1 cells differentiated into white adipocytes with a specific medium (DMEM 10% calf serum 1% penicillin/streptomycin 500 uM 3isobutyl1 methylxanthine 10ug/ml insulin 250 nM dexmethasone 8 ug/ml biotin and 4 ug/ml pantothenic acid). Fully differentiated white adipocytes were treated after 10 days with different genistein doses (10-50-100-200 uM) for 24-48h or left untreated. Two specific ER-beta and PPAR-gamma receptor inhibitors were also used to understand if genistein effects are mediated by the estrogen or the PPAR receptor. Also a CRISPR/Cas9 approach was used to delete either ER-beta or PPAR-gamma to clarify which receptor is involved in genistein action. Intracellular lipid accumulation was determined by oil-red-O staining after 24 and 48hours of treatment. The expression of UCP1 estrogen receptor alpha and beta PPARalpha and gamma DIO2 (Type II iodothyronine deiodinase) PRDM16 (PR domain containing 16) and CIDEA (cell death inducing DNA fragmentation factor) were evaluated by qPCR after 24 and 48hours of genistein treatment. -
Letters to the Editor
LETTERS TO THE EDITOR The closely related rare and severe acute myeloid leukemias carrying EVI1 or PRDM16 rearrangements share singular biological features In a recent issue of Haematologica , Matsuo et al .1 pinpoint the pejorative effect of EVI1 overexpression in 18 acute myeloid leukemias (AML) with MLL rearrangements. However, EVI1 overexpression has also been reported in patients with translocations involving chromosome 3 and the EVI1 gene. 2,3 Because of the poor prognosis associated to these anomalies, it is important to investigate them at an early stage in order to adapt patient management. Indeed, previous reports 4-6 and the 2008 WHO classification 7 indi - cate that EVI1-rearranged (EVI1-r) AML display typical fea - tures, such as absence of thrombopenia, atypical megakary - Figure 1. Algorithm for the suspicion of EVI1 and PRDM16 AMLs. ocytes and multilineage dysplasia 2-4 which can be detected by current diagnostic reference methods. In this line, we compared a cohort of 17 EVI1-r AML, aged between 8 and 79-years old (median 54 years) to 1822 other cases of AML months. diagnosed in the same laboratory over 14 years. At diagno - This study consolidates the unusual base-line character - sis, there were similar hemoglobin levels or white blood istics and clinical features of EVI1-r AML cases. Moreover, cell counts in both groups. Median platelet counts were it indicates a very low rate of MPO expression in EVI1-r 9 9 123x10 /L, higher than 100x10 /L in 53% of EVI1-r AML AML patients. It is interesting to note that relationships patients, compared to 25% in the control AML population have been reported between EVI1 expression and MPO (P=0.02). -
Genome-Wide DNA Methylation Analysis of KRAS Mutant Cell Lines Ben Yi Tew1,5, Joel K
www.nature.com/scientificreports OPEN Genome-wide DNA methylation analysis of KRAS mutant cell lines Ben Yi Tew1,5, Joel K. Durand2,5, Kirsten L. Bryant2, Tikvah K. Hayes2, Sen Peng3, Nhan L. Tran4, Gerald C. Gooden1, David N. Buckley1, Channing J. Der2, Albert S. Baldwin2 ✉ & Bodour Salhia1 ✉ Oncogenic RAS mutations are associated with DNA methylation changes that alter gene expression to drive cancer. Recent studies suggest that DNA methylation changes may be stochastic in nature, while other groups propose distinct signaling pathways responsible for aberrant methylation. Better understanding of DNA methylation events associated with oncogenic KRAS expression could enhance therapeutic approaches. Here we analyzed the basal CpG methylation of 11 KRAS-mutant and dependent pancreatic cancer cell lines and observed strikingly similar methylation patterns. KRAS knockdown resulted in unique methylation changes with limited overlap between each cell line. In KRAS-mutant Pa16C pancreatic cancer cells, while KRAS knockdown resulted in over 8,000 diferentially methylated (DM) CpGs, treatment with the ERK1/2-selective inhibitor SCH772984 showed less than 40 DM CpGs, suggesting that ERK is not a broadly active driver of KRAS-associated DNA methylation. KRAS G12V overexpression in an isogenic lung model reveals >50,600 DM CpGs compared to non-transformed controls. In lung and pancreatic cells, gene ontology analyses of DM promoters show an enrichment for genes involved in diferentiation and development. Taken all together, KRAS-mediated DNA methylation are stochastic and independent of canonical downstream efector signaling. These epigenetically altered genes associated with KRAS expression could represent potential therapeutic targets in KRAS-driven cancer. Activating KRAS mutations can be found in nearly 25 percent of all cancers1. -
Transcription Factors That Govern Development and Disease: an Achilles Heel in Cancer
G C A T T A C G G C A T genes Review Transcription Factors That Govern Development and Disease: An Achilles Heel in Cancer Dhananjay Huilgol , Prabhadevi Venkataramani , Saikat Nandi * and Sonali Bhattacharjee * Bungtown Road, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA; [email protected] (D.H.); [email protected] (P.V.) * Correspondence: [email protected] (S.N.); [email protected] (S.B.) Received: 15 September 2019; Accepted: 8 October 2019; Published: 12 October 2019 Abstract: Development requires the careful orchestration of several biological events in order to create any structure and, eventually, to build an entire organism. On the other hand, the fate transformation of terminally differentiated cells is a consequence of erroneous development, and ultimately leads to cancer. In this review, we elaborate how development and cancer share several biological processes, including molecular controls. Transcription factors (TF) are at the helm of both these processes, among many others, and are evolutionarily conserved, ranging from yeast to humans. Here, we discuss four families of TFs that play a pivotal role and have been studied extensively in both embryonic development and cancer—high mobility group box (HMG), GATA, paired box (PAX) and basic helix-loop-helix (bHLH) in the context of their role in development, cancer, and their conservation across several species. Finally, we review TFs as possible therapeutic targets for cancer and reflect on the importance of natural resistance against cancer in certain organisms, yielding knowledge regarding TF function and cancer biology. Keywords: transcription factors; embryonic development; evolution; cancer; clinical trials; high mobility group box (HMG); basic helix loop helix (bHLH); paired box (Pax); GATA 1. -
ETV6 Mutations in Early Immature Human T Cell Leukemias
Published December 12, 2011 Brief Definitive Report ETV6 mutations in early immature human T cell leukemias Pieter Van Vlierberghe,1 Alberto Ambesi-Impiombato,1 Arianne Perez-Garcia,1 J. Erika Haydu,1 Isaura Rigo,1 Michael Hadler,1 Valeria Tosello,1 Giusy Della Gatta,1 Elisabeth Paietta,4 Janis Racevskis,4 Peter H. Wiernik,4 Selina M. Luger,5 Jacob M. Rowe,6 Montserrat Rue,7 and Adolfo A. Ferrando1,2,3 1Institute for Cancer Genetics, 2Department of Pediatrics, and 3Department of Pathology, Columbia University Medical Center, New York, NY 10032 4Montefiore Medical Center North, Bronx, New York, NY 10467 5Hematologic Malignancies and Stem Cell Transplant Program, Hematology-Oncology Division, University of Pennsylvania Medical Center, Philadelphia, PA 19104 6 Rambam Medical Center, Haifa 31096, Israel Downloaded from 7Department of Basic Medical Sciences, University of Lleida, Lleida 25003, Spain Early immature T cell acute lymphoblastic leukemias (T-ALLs) account for 5–10% of pediatric T-ALLs and are associated with poor prognosis. However, the genetic defects that drive the biology of these tumors remain largely unknown. In this study, analysis of micro- array gene expression signatures in adult T-ALL demonstrated a high prevalence of early immature leukemias and revealed a close relationship between these tumors and myeloid jem.rupress.org leukemias. Many adult immature T-ALLs harbored mutations in myeloid-specific oncogenes and tumor suppressors including IDH1, IDH2, DNMT3A, FLT3, and NRAS. Moreover, we identifiedETV6 mutations as a novel genetic lesion uniquely present in immature adult T-ALL. Our results demonstrate that early immature adult T-ALL represents a heterogeneous category of leukemias characterized by the presence of overlapping myeloid and T-ALL on May 30, 2015 characteristics, and highlight the potential role of ETV6 mutations in these tumors. -
Evidence That the WNT-Inducible Growth Arrest- Specific Gene 1 Encodes an Antagonist of Sonic Hedgehog Signaling in the Somite
Evidence that the WNT-inducible growth arrest- specific gene 1 encodes an antagonist of sonic hedgehog signaling in the somite Catherine S. Lee*, Laura Buttitta*, and Chen-Ming Fan† Department of Embryology, Carnegie Institution of Washington, 115 West University Parkway, Baltimore, MD 21210 Communicated by Donald D. Brown, Carnegie Institution of Washington, Baltimore, MD, August 8, 2001 (received for review July 16, 2001) The dorsal–ventral polarity of the somite is controlled by antago- Materials and Methods ͞ nistic signals from the dorsal neural tube surface ectoderm, me- cDNA Library Screen. A cDNA library was constructed in pMT21 diated by WNTs, and from the ventral notochord, mediated by with the use of poly(A)ϩ RNA isolated from the caudal quarter sonic hedgehog (SHH). Each factor can act over a distance greater of 180 embryonic day (E)9.5 CD1 mouse embryos. COS cells than a somite diameter in vitro, suggesting they must limit each were transfected with 174 pools (1,000 cDNAs per pool) of the other’s actions within their own patterning domains in vivo.We library with Lipofectamine (GIBCO͞BRL) and screened for show here that the growth-arrest specific gene 1 (Gas1), which is SHH-N-alkaline phosphatase (SHH-N-AP) binding activity expressed in the dorsal somite, is induced by WNTs and encodes a (14). Positive pools were rescreened to obtain single clones. protein that can bind to SHH. Furthermore, ectopic expression of SHH-N-AP and SHH-N-Fc were fusions of SHH-N (amino acids Gas1 in presomitic cells attenuates the response of these cells to 1–198) to AP and to Ig constant region (Fc) (15). -
The Regulation of Lunatic Fringe During Somitogenesis
THE REGULATION OF LUNATIC FRINGE DURING SOMITOGENESIS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Emily T. Shifley ***** The Ohio State University 2009 Dissertation Committee: Approved by Professor Susan Cole, Advisor Professor Christine Beattie _________________________________ Professor Mark Seeger Advisor Graduate Program in Molecular Genetics Professor Michael Weinstein ABSTRACT Somitogenesis is the morphological hallmark of vertebrate segmentation. Somites bud from the presomitic mesoderm (PSM) in a sequential, periodic fashion and give rise to the rib cage, vertebrae, and dermis and muscles of the back. The regulation of somitogenesis is complex. In the posterior region of the PSM, a segmentation clock operates to organize cohorts of cells into presomites, while in the anterior region of the PSM the presomites are patterned into rostral and caudal compartments (R/C patterning). Both of these stages of somitogenesis are controlled, at least in part, by the Notch pathway and Lunatic fringe (Lfng), a glycosyltransferase that modifies the Notch receptor. To dissect the roles played by Lfng during somitogenesis, we created a novel allele that lacks cyclic Lfng expression within the segmentation clock, but that maintains expression during R/C somite patterning (Lfng∆FCE1). Lfng∆FCE1/∆FCE1 mice have severe defects in their anterior vertebrae and rib cages, but relatively normal sacral and tail vertebrae, unlike Lfng knockouts. Segmentation clock function is differentially affected by the ∆FCE1 deletion; during anterior somitogenesis the expression patterns of many clock genes are disrupted, while during posterior somitogenesis, certain clock components have recovered. R/C patterning occurs relatively normally in Lfng∆FCE1/∆FCE1 embryos, likely contributing to the partial phenotype rescue, and confirming that Lfng ii plays separate roles in the two regions of the PSM. -
The Facebase Consortium: a Comprehensive Program To
Manuscript Click here to view linked References The FaceBase Consortium: A Comprehensive Program to Facilitate Craniofacial Research Harry Hochheiser1*, Bruce J. Aronow2, Kristin Artinger3, Terri H.Beaty4, James F. Brinkley5, Yang Chai6, David Clouthier3, Michael L. Cunningham7, Michael Dixon8, Leah Rae Donahue9, Scott E. Fraser10, Junichi Iwata6, Mary L. Marazita11, Jeffrey C. Murray12, Stephen Murray9, John Postlethwait13, Steven Potter14, Linda Shapiro5, Richard Spritz15, Axel Visel16, Seth M. Weinberg17 and Paul A. Trainor18*, for the FaceBase Consortium. 1. Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh PA 15232 USA 2. Divisions of Biomedical Informatics and Developmental Biology, Center for Computational Medicine, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, CHRF 8504, 3333 Burnet Ave Cincinnati, OH 45229 USA 3. Department of Craniofacial Biology, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045 4. Department of Epidemiology, Johns Hopkins University, 615 N. Wolfe Street Baltimore, MD. 21205 USA 5. Department of Computer Science and Engineering, University of Washington, Box 352350 Seattle, WA 98195-2350 USA 6. Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033 7. Seattle Children’s Hospital, 4800 Sand Point Way NE, Seattle, WA 98105 8. Faculty of Medical and Human Sciences, Manchester Academic Health Sciences Centre, and Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester, M13 9PT, England 1 9. Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609 USA 10. Biological Imaging Center Beckman Institute 133, M/C 139-74 California Institute of Technology Pasadena, CA 91125 11. -
The Suppressive Effects of 1,25-Dihydroxyvitamin D3 and Vitamin D Receptor on Brown Adipocyte Differentiation and Mitochondrial Respiration
University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Masters Theses Graduate School 8-2014 The Suppressive Effects of 1,25-dihydroxyvitamin D3 and Vitamin D Receptor on Brown Adipocyte Differentiation and Mitochondrial Respiration Carolyn Jeanne Ricciardi University of Tennessee - Knoxville, [email protected] Follow this and additional works at: https://trace.tennessee.edu/utk_gradthes Part of the Molecular, Genetic, and Biochemical Nutrition Commons Recommended Citation Ricciardi, Carolyn Jeanne, "The Suppressive Effects of 1,25-dihydroxyvitamin D3 and Vitamin D Receptor on Brown Adipocyte Differentiation and Mitochondrial Respiration. " Master's Thesis, University of Tennessee, 2014. https://trace.tennessee.edu/utk_gradthes/2876 This Thesis is brought to you for free and open access by the Graduate School at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Masters Theses by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. To the Graduate Council: I am submitting herewith a thesis written by Carolyn Jeanne Ricciardi entitled "The Suppressive Effects of 1,25-dihydroxyvitamin D3 and Vitamin D Receptor on Brown Adipocyte Differentiation and Mitochondrial Respiration." I have examined the final electronic copy of this thesis for form and content and recommend that it be accepted in partial fulfillment of the equirr ements for the degree of Master of Science, with a major in Nutrition. -
Single Cell Regulatory Landscape of the Mouse Kidney Highlights Cellular Differentiation Programs and Disease Targets
ARTICLE https://doi.org/10.1038/s41467-021-22266-1 OPEN Single cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets Zhen Miao 1,2,3,8, Michael S. Balzer 1,2,8, Ziyuan Ma 1,2,8, Hongbo Liu1,2, Junnan Wu 1,2, Rojesh Shrestha 1,2, Tamas Aranyi1,2, Amy Kwan4, Ayano Kondo 4, Marco Pontoglio 5, Junhyong Kim6, ✉ Mingyao Li 7, Klaus H. Kaestner2,4 & Katalin Susztak 1,2,4 1234567890():,; Determining the epigenetic program that generates unique cell types in the kidney is critical for understanding cell-type heterogeneity during tissue homeostasis and injury response. Here, we profile open chromatin and gene expression in developing and adult mouse kidneys at single cell resolution. We show critical reliance of gene expression on distal regulatory elements (enhancers). We reveal key cell type-specific transcription factors and major gene- regulatory circuits for kidney cells. Dynamic chromatin and expression changes during nephron progenitor differentiation demonstrates that podocyte commitment occurs early and is associated with sustained Foxl1 expression. Renal tubule cells follow a more complex differentiation, where Hfn4a is associated with proximal and Tfap2b with distal fate. Mapping single nucleotide variants associated with human kidney disease implicates critical cell types, developmental stages, genes, and regulatory mechanisms. The single cell multi-omics atlas reveals key chromatin remodeling events and gene expression dynamics associated with kidney development. 1 Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. 2 Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA. -
Genome-Wide DNA Methylation Analysis Reveals Molecular Subtypes of Pancreatic Cancer
www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 17), pp: 28990-29012 Research Paper Genome-wide DNA methylation analysis reveals molecular subtypes of pancreatic cancer Nitish Kumar Mishra1 and Chittibabu Guda1,2,3,4 1Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, 68198, USA 2Bioinformatics and Systems Biology Core, University of Nebraska Medical Center, Omaha, NE, 68198, USA 3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA 4Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA Correspondence to: Chittibabu Guda, email: [email protected] Keywords: TCGA, pancreatic cancer, differential methylation, integrative analysis, molecular subtypes Received: October 20, 2016 Accepted: February 12, 2017 Published: March 07, 2017 Copyright: Mishra et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Pancreatic cancer (PC) is the fourth leading cause of cancer deaths in the United States with a five-year patient survival rate of only 6%. Early detection and treatment of this disease is hampered due to lack of reliable diagnostic and prognostic markers. Recent studies have shown that dynamic changes in the global DNA methylation and gene expression patterns play key roles in the PC development; hence, provide valuable insights for better understanding the initiation and progression of PC. In the current study, we used DNA methylation, gene expression, copy number, mutational and clinical data from pancreatic patients. -
Androgen Modulation of XBP1 Is Functionally Driving Part of the AR Transcriptional Program
27 2 Endocrine-Related S Stelloo, S Linder et al. AR and XBP1 transcription 27:2 67–79 Cancer factor activity RESEARCH Androgen modulation of XBP1 is functionally driving part of the AR transcriptional program Suzan Stelloo1,*, Simon Linder1,*, Ekaterina Nevedomskaya1,2, Eider Valle-Encinas1, Iris de Rink3, Lodewyk F A Wessels2,4, Henk van der Poel5, Andries M Bergman6,7 and Wilbert Zwart1,8 1Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands 2Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands 3Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands 4Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands 5Division of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands 6Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, The Netherlands 7Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands 8Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands Correspondence should be addressed to A M Bergman or W Zwart: [email protected] or [email protected] *(S Stelloo and S Linder contributed equally to this work) Abstract Prostate cancer development and progression is largely dependent on androgen receptor Key Words (AR) signaling. AR is a hormone-dependent transcription factor, which binds to thousands f androgen receptor of sites throughout the human genome to regulate expression of directly responsive f XBP1 splicing genes, including pro-survival genes that enable tumor cells to cope with increased f ChIP-seq cellular stress. ERN1 and XBP1 – two key players of the unfolded protein response (UPR) f unfolded protein response – are among such stress-associated genes.