Regulation of T cell receptor beta gene rearrangements and allelic exclusion by the helix-loop-helix protein, E47.
Allelic exclusion of antigen-receptor genes is ensured primarily by monoallelic locus activation upon rearrangement and subsequently by feedback inhibition of continued rearrangement. Here, we demonstrated that the basic helix-loop-helix protein, E47, promoted T cell receptor beta (TCRbeta) gene rearrangement by directly binding to target gene segments to increase chromatin accessibility in a dosage-sensitive manner. Feedback signaling abrogated E47 binding, leading to a decline in accessibility. Conversely, enforced expression of E47 induced TCRbeta gene rearrangement by antagonizing feedback inhibition. Thus, the abundance of E47 is rate limiting in locus activation, and feedback signaling downregulates E47 activity to ensure allelic exclusion.
Agata
Yasutoshi
Y
Horizontal Medical Research Organization, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. yagata@mch.pref.osaka.jp
Tamaki
Nobuyuki
N
Sakamoto
Shuji
S
Ikawa
Tomokatsu
T
Masuda
Kyoko
K
Kawamoto
Hiroshi
H
Murre
Cornelis
C
D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D025461:Feedback, Physiological; D015329:Gene Rearrangement, T-Lymphocyte; D019674:Genes, T-Cell Receptor beta; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology; D051820:TCF Transcription Factors / Q000502:physiology*; D058125:Transcription Factor 7-Like 1 Protein
D051792:Basic Helix-Loop-Helix Proteins; D011948:Receptors, Antigen, T-Cell; D051820:TCF Transcription Factors; D058125:Transcription Factor 7-Like 1 Protein; C489532:Tcf12 protein, mouse; C075668:Tcf3 protein, mouse; C544913:Tcf7l1 protein, mouse