학술논문
BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.
Document Type
Academic Journal
Author
Afzali B; Lymphocyte Cell Biology Section (Molecular Immunology and Inflammation Branch), Biodata Mining and Discovery Section and Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.; MRC Centre for Transplantation, King's College London, London, UK.; Grönholm J; Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, Biological Imaging Section (Research Technologies Branch) and Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Vandrovcova J; Molecular Neuroscience, Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK.; Department of Medicine, Imperial College London, London, UK.; O'Brien C; Department of Medicine, Imperial College London, London, UK.; Sun HW; Lymphocyte Cell Biology Section (Molecular Immunology and Inflammation Branch), Biodata Mining and Discovery Section and Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Vanderleyden I; Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK.; Davis FP; Lymphocyte Cell Biology Section (Molecular Immunology and Inflammation Branch), Biodata Mining and Discovery Section and Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Khoder A; Department of Medicine, Imperial College London, London, UK.; Zhang Y; Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, Biological Imaging Section (Research Technologies Branch) and Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Hegazy AN; Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK.; Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.; Villarino AV; Lymphocyte Cell Biology Section (Molecular Immunology and Inflammation Branch), Biodata Mining and Discovery Section and Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Palmer IW; Lymphocyte Cell Biology Section (Molecular Immunology and Inflammation Branch), Biodata Mining and Discovery Section and Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Kaufman J; Lymphocyte Cell Biology Section (Molecular Immunology and Inflammation Branch), Biodata Mining and Discovery Section and Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Watts NR; Lymphocyte Cell Biology Section (Molecular Immunology and Inflammation Branch), Biodata Mining and Discovery Section and Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Kazemian M; Department of Biochemistry and Department of Computer Science, Purdue University, West Lafayette, Indiana, USA.; Kamenyeva O; Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, Biological Imaging Section (Research Technologies Branch) and Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Keith J; Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK.; Sayed A; Department of Medicine, Imperial College London, London, UK.; Kasperaviciute D; Imperial BRC Genomics Facility, Hammersmith Hospital, London, UK.; Mueller M; Imperial BRC Genomics Facility, Hammersmith Hospital, London, UK.; Hughes JD; Merck Research Laboratories, Merck &Co. Inc., Boston, Massachusetts, USA.; Fuss IJ; Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, Biological Imaging Section (Research Technologies Branch) and Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Sadiyah MF; Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK.; Montgomery-Recht K; Clinical Research Directorate/CMRP, Leidos Biomedical Research Inc., NCI at Frederick, Frederick, Maryland, USA.; McElwee J; Merck Research Laboratories, Merck &Co. Inc., Boston, Massachusetts, USA.; Restifo NP; National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.; Strober W; Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, Biological Imaging Section (Research Technologies Branch) and Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Linterman MA; Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK.; Wingfield PT; Lymphocyte Cell Biology Section (Molecular Immunology and Inflammation Branch), Biodata Mining and Discovery Section and Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Uhlig HH; Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK.; Department of Paediatrics, University of Oxford, Oxford, UK.; Roychoudhuri R; Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK.; Aitman TJ; Department of Medicine, Imperial College London, London, UK.; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.; Kelleher P; Department of Medicine, Imperial College London, London, UK.; Lenardo MJ; Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, Biological Imaging Section (Research Technologies Branch) and Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.; O'Shea JJ; Lymphocyte Cell Biology Section (Molecular Immunology and Inflammation Branch), Biodata Mining and Discovery Section and Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.; Cooper N; Department of Medicine, Imperial College London, London, UK.; Laurence ADJ; Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK.; Department of Haematology, Northern Centre for Cancer Care, Newcastle upon Tyne, UK.
Source
Publisher: Nature America Inc Country of Publication: United States NLM ID: 100941354 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1529-2916 (Electronic) Linking ISSN: 15292908 NLM ISO Abbreviation: Nat Immunol Subsets: MEDLINE
Subject
Language
English
Abstract
The transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.