Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes.
Type 1 diabetes may result from a breakdown in peripheral tolerance that is partially controlled by the expression of peripheral tissue antigens (PTAs) in lymph nodes. Here we show that the transcriptional regulator Deaf1 controls the expression of genes encoding PTAs in the pancreatic lymph nodes (PLNs). The expression of canonical Deaf1 was lower, whereas that of an alternatively spliced variant was higher, during the onset of destructive insulitis in the PLNs of nonobese diabetic (NOD) mice. We identified an equivalent variant Deaf1 isoform in the PLNs of patients with type 1 diabetes. Both the NOD mouse and human Deaf1 variant isoforms suppressed PTA expression by inhibiting the transcriptional activity of canonical Deaf1. Lower PTA expression resulting from the alternative splicing of DEAF1 may contribute to the pathogenesis of type 1 diabetes.
Yip
Linda
L
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.
Su
Leon
L
Sheng
Deqiao
D
Chang
Pearl
P
Atkinson
Mark
M
Czesak
Margaret
M
Albert
Paul R
PR
Collier
Ai-Ris
AR
Turley
Shannon J
SJ
Fathman
C Garrison
CG
Creusot
Rémi J
RJ
D017398:Alternative Splicing; D000818:Animals; D000941:Antigens / Q000235:genetics*; D001483:Base Sequence; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology*; D010179:Pancreas / Q000276:immunology*; D020033:Protein Isoforms; D014157:Transcription Factors
D000941:Antigens; C116013:DEAF1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D014157:Transcription Factors