2. Academic Validation
  3. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients

Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients

  • J Exp Med. 2021 Jul 5;218(7):e20201750. doi: 10.1084/jem.20201750.
Carole Le Coz 1,  David N Nguyen 2 3 4 5 6,  Chun Su 7 8,  Brian E Nolan 9 10,  Amanda V Albrecht 11,  Suela Xhani 11,  Di Sun 1,  Benjamin Demaree 12 13,  Piyush Pillarisetti 1,  Caroline Khanna 1,  Francis Wright 2 3,  Peixin Amy Chen 3 4 5 6,  Samuel Yoon 1,  Amy L Stiegler 14,  Kelly Maurer 1,  James P Garifallou 15,  Amy Rymaszewski 16,  Steven H Kroft 17,  Timothy S Olson 18 19,  Alix E Seif 18 19,  Gerald Wertheim 20 21,  Struan F A Grant 7 19 22 23,  Linda T Vo 4 5,  Jennifer M Puck 24 25 26,  Kathleen E Sullivan 1 19 27,  John M Routes 16,  Viktoria Zakharova 28,  Anna Shcherbina 29,  Anna Mukhina 29,  Natasha L Rudy 30,  Anna C E Hurst 30 31,  T Prescott Atkinson 31,  Titus J Boggon 14 32,  Hakon Hakonarson 15 19,  Adam R Abate 12 13 33,  Joud Hajjar 34 35,  Sarah K Nicholas 34 35,  James R Lupski 36 37 38,  James Verbsky 16,  Ivan K Chinn 34 35,  Michael V Gonzalez 15,  Andrew D Wells 8 20 27,  Alex Marson 2 3 4 5 6 33 39,  Gregory M K Poon 11,  Neil Romberg 1 19 27
Affiliations

Affiliations

  • 1 Division of Immunology and Allergy, Children's Hospital of Philadelphia, Philadelphia, PA.
  • 2 Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA.
  • 3 Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA.
  • 4 Diabetes Center, University of California San Francisco, San Francisco, CA.
  • 5 Innovative Genomics Institute, University of California Berkeley, Berkeley, CA.
  • 6 Gladstone-University of California San Francisco Institute of Genomic Immunology, San Francisco, CA.
  • 7 Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA.
  • 8 Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.
  • 9 Division of Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
  • 10 Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL.
  • 11 Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.
  • 12 Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA.
  • 13 University of California Berkeley-University of California San Francisco Graduate Program in Bioengineering, University of California, San Francisco, CA.
  • 14 Departments of Pharmacology, Yale University, New Haven, CT.
  • 15 Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA.
  • 16 Division of Allergy and Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.
  • 17 Department of Pathology, Medical College of Wisconsin, Milwaukee, WI.
  • 18 Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA.
  • 19 Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA.
  • 20 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA.
  • 21 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 22 Division of Diabetes and Endocrinology, Children's Hospital of Philadelphia, Philadelphia, PA.
  • 23 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 24 Division of Allergy, Immunology, and Bone Marrow Transplantation, Department of Pediatrics, University of California, San Francisco, CA.
  • 25 University of California San Francsico Institute for Human Genetics and Smith Cardiovascular Research Institute, University of California, San Francisco, CA.
  • 26 UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.
  • 27 Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
  • 28 Laboratory of Molecular Biology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
  • 29 Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
  • 30 Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.
  • 31 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.
  • 32 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT.
  • 33 Chan Zuckerberg Biohub, San Francisco, CA.
  • 34 William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX.
  • 35 Department of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX.
  • 36 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
  • 37 Texas Children's Hospital, Houston, TX.
  • 38 Baylor-Hopkins Center for Mendelian Genomics, Houston, TX.
  • 39 Parker Institute for Cancer Immunotherapy, San Francisco, CA.
PMID: 33951726 DOI: 10.1084/jem.20201750
Abstract

The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.

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