Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

May 6, 2021

Contributor: Carole Le Coz,David N Nguyen,Chun Su,Brian E Nolan,Amanda V Albrecht,Suela Xhani,Di Sun,Benjamin Demaree,Piyush Pillarisetti,Caroline Khanna,Francis Wright,Peixin Amy Chen,Samuel Yoon,Amy L Stiegler,Kelly Maurer,James P Garifallou,Amy Rymaszewski,Steven H Kroft,Timothy S Olson,Alix E Seif,Gerald Wertheim,Struan F A Grant,Linda T Vo,Jennifer M Puck,Kathleen E Sullivan,John M Routes,Viktoria Zakharova,Anna Shcherbina,Anna Mukhina,Natasha L Rudy,Anna C E Hurst,T Prescott Atkinson,Titus J Boggon,Hakon Hakonarson,Adam R Abate,Joud Hajjar,Sarah K Nicholas,James R Lupski,James Verbsky,Ivan K Chinn,Michael V Gonzalez,Andrew D Wells,Alex Marson,Gregory M K Poon,Neil Romberg

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.
© 2021 Le Coz et al.

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About The Expert

Carole Le Coz

Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA.

David N Nguyen

Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA.

Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA.

Diabetes Center, University of California San Francisco, San Francisco, CA.

Innovative Genomics Institute, University of California Berkeley, Berkeley, CA.

Gladstone-University of California San Francisco Institute of Genomic Immunology, San Francisco, CA.

Chun Su

Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA.

Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA.

Brian E Nolan

Division of Rheumatology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL.

Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL.

Amanda V Albrecht

Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.

Suela Xhani

Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.

Di Sun

Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA.

Benjamin Demaree

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA.

University of California Berkeley-University of California San Francisco Graduate Program in Bioengineering, University of California, San Francisco, CA.

Piyush Pillarisetti

Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA.

Caroline Khanna

Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA.

Francis Wright

Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA.

Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA.

Peixin Amy Chen

Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA.

Diabetes Center, University of California San Francisco, San Francisco, CA.

Innovative Genomics Institute, University of California Berkeley, Berkeley, CA.

Gladstone-University of California San Francisco Institute of Genomic Immunology, San Francisco, CA.

Samuel Yoon

Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA.

Amy L Stiegler

Departments of Pharmacology, Yale University, New Haven, CT.

Kelly Maurer

Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA.

James P Garifallou

Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA.

Amy Rymaszewski

Division of Allergy and Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.

Steven H Kroft

Department of Pathology, Medical College of Wisconsin, Milwaukee, WI.

Timothy S Olson

Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA.

Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA.

Alix E Seif

Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA.

Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA.

Gerald Wertheim

Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Struan F A Grant

Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA.

Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA.

Division of Diabetes and Endocrinology, Children’s Hospital of Philadelphia, Philadelphia, PA.

Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Linda T Vo

Diabetes Center, University of California San Francisco, San Francisco, CA.

Innovative Genomics Institute, University of California Berkeley, Berkeley, CA.

Jennifer M Puck

Division of Allergy, Immunology, and Bone Marrow Transplantation, Department of Pediatrics, University of California, San Francisco, CA.

University of California San Francsico Institute for Human Genetics and Smith Cardiovascular Research Institute, University of California, San Francisco, CA.

UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.

Kathleen E Sullivan

Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA.

Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA.

Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

John M Routes

Division of Allergy and Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.

Viktoria Zakharova

Laboratory of Molecular Biology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Anna Shcherbina

Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Anna Mukhina

Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.

Natasha L Rudy

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.

Anna C E Hurst

Department of Genetics, University of Alabama at Birmingham, Birmingham, AL.

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.

T Prescott Atkinson

Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL.

Titus J Boggon

Departments of Pharmacology, Yale University, New Haven, CT.

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT.

Hakon Hakonarson

Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA.

Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA.

Adam R Abate

Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA.

University of California Berkeley-University of California San Francisco Graduate Program in Bioengineering, University of California, San Francisco, CA.

Chan Zuckerberg Biohub, San Francisco, CA.

Joud Hajjar

William T. Shearer Center for Human Immunobiology, Texas Children’s Hospital, Houston, TX.

Department of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX.

Sarah K Nicholas

William T. Shearer Center for Human Immunobiology, Texas Children’s Hospital, Houston, TX.

Department of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX.

James R Lupski

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.

Texas Children’s Hospital, Houston, TX.

Baylor-Hopkins Center for Mendelian Genomics, Houston, TX.

James Verbsky

Division of Allergy and Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.

Ivan K Chinn

William T. Shearer Center for Human Immunobiology, Texas Children’s Hospital, Houston, TX.

Department of Immunology, Allergy and Rheumatology, Baylor College of Medicine, Houston, TX.

Michael V Gonzalez

Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA.

Andrew D Wells

Center for Spatial and Functional Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA.

Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA.

Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Alex Marson

Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, CA.

Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA.

Diabetes Center, University of California San Francisco, San Francisco, CA.

Innovative Genomics Institute, University of California Berkeley, Berkeley, CA.

Gladstone-University of California San Francisco Institute of Genomic Immunology, San Francisco, CA.

Chan Zuckerberg Biohub, San Francisco, CA.

Parker Institute for Cancer Immunotherapy, San Francisco, CA.

Gregory M K Poon

Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA.

Neil Romberg

Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, PA.

Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA.

Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

References

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Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.

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About The Expert

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