title: Super-enhancers delineate disease-associated regulatory nodes in T cells.
abstract: Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity. Super-enhancers (SEs), also known as stretch-enhancers, are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease. CD4(+) T cells are critical for host defence and autoimmunity. Here we analysed maps of mouse T-cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. Nonetheless, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T-cell SE, revealing a network in which SE-associated genes critical for T-cell biology are repressed by BACH2. Disease-associated single-nucleotide polymorphisms for immune-mediated disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs versus typical enhancers or SEs in other cell lineages. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately altered the expression of rheumatoid arthritis risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a 'guardian' transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows the unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.
authors: Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors: Golnaz
authors: G
authors: Vahedi
authors: Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors: Yuka
authors: Y
authors: Kanno
authors: Translational Immunology Section, NIAMS, NIH, Bethesda, Maryland 20892, USA.
authors: Yasuko
authors: Y
authors: Furumoto
authors: Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors: Kan
authors: K
authors: Jiang
authors: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
authors: Stephen C J
authors: SC
authors: Parker
authors: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
authors: Michael R
authors: MR
authors: Erdos
authors: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors: Sean R
authors: SR
authors: Davis
authors: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors: Rahul
authors: R
authors: Roychoudhuri
authors: Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
authors: Nicholas P
authors: NP
authors: Restifo
authors: Translational Immunology Section, NIAMS, NIH, Bethesda, Maryland 20892, USA.
authors: Massimo
authors: M
authors: Gadina
authors: The Jackson Laboratory for Genomic Medicine and Department of Genetic and Development Biology, University of Connecticut, Farmington, Connecticut 06030, USA.
authors: Zhonghui
authors: Z
authors: Tang
authors: The Jackson Laboratory for Genomic Medicine and Department of Genetic and Development Biology, University of Connecticut, Farmington, Connecticut 06030, USA.
authors: Yijun
authors: Y
authors: Ruan
authors: Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA.
authors: Francis S
authors: FS
authors: Collins
authors: Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, NIH, Bethesda, Maryland 20892, USA.
authors: Vittorio
authors: V
authors: Sartorelli
authors: Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.
authors: John J
authors: JJ
authors: O'Shea
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D010880:Piperidines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D022661:RNA, Untranslated / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D014158:Transcription, Genetic / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D053616:Janus Kinase 3; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D022661:RNA, Untranslated; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C102109:Bach2 protein, mouse; C479163:tofacitinib