Multiple layers of transcriptional regulation by PLZF in NKT-cell development.
The transcription factor PLZF [promyelocytic leukemia zinc finger, encoded by zinc finger BTB domain containing 16 (Zbtb16)] is induced during the development of innate and innate-like lymphocytes to direct their acquisition of a T-helper effector program, but the molecular mechanisms involved are poorly understood. Using biotinylation-based ChIP-seq and microarray analysis of both natural killer T (NKT) cells and PLZF-transgenic thymocytes, we identified several layers of regulation of the innate-like NKT effector program. First, PLZF bound and regulated genes encoding cytokine receptors as well as homing and adhesion receptors; second, PLZF bound and activated T-helper-specific transcription factor genes that in turn control T-helper-specific programs; finally, PLZF bound and suppressed the transcription of Bach2, a potent general repressor of effector differentiation in naive T cells. These findings reveal the multilayered architecture of the transcriptional program recruited by PLZF and elucidate how a single transcription factor can drive the developmental acquisition of a broad effector program.
Committee on Immunology, University of Chicago, Chicago, IL 60637; Department of Pathology, University of Chicago, Chicago, IL 60637;
Ai-Ping
AP
Mao
Committee on Immunology, University of Chicago, Chicago, IL 60637; Department of Pathology, University of Chicago, Chicago, IL 60637;
Michael G
MG
Constantinides
Committee on Immunology, University of Chicago, Chicago, IL 60637; Department of Pathology, University of Chicago, Chicago, IL 60637;
Rebecca
R
Mathew
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China;
Zhixiang
Z
Zuo
Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
Xiaoting
X
Chen
Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
Matthew T
MT
Weirauch
Committee on Immunology, University of Chicago, Chicago, IL 60637; Department of Pathology, University of Chicago, Chicago, IL 60637; abendela@bsd.uchicago.edu.
Albert
A
Bendelac
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D050657:Core Binding Factor alpha Subunits / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000502:physiology*; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism
C102109:Bach2 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D050657:Core Binding Factor alpha Subunits; D016207:Cytokines; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D050783:Proto-Oncogene Proteins c-ets; D019707:Receptors, Chemokine; C513267:Zbtb16 protein, mouse
NKT; PLZF; development; lymphocyte