Abstract
An intronic silencer, S4, in the Cd4 gene has been shown to be responsible for the helper-lineage-specific expression of CD4; S4 requires Runx complex binding to exert its silencer function against the enhancer-mediated Cd4 activation by modulating the epigenetic state of the Cd4 gene. Here we identify a late-acting maturation enhancer. Bcl11b plays essential roles for activation of both the early-acting proximal enhancer and maturation enhancer of Cd4. Notably, Runx complexes suppress these enhancers by distinct mechanisms. Whereas repression of the proximal enhancer depends on the S4 silencer, the maturation enhancer is repressed by Runx in the absence of S4. Moreover, ThPOK, known to antagonize S4-mediated Cd4 repression, assists Runx complexes to restrain maturation enhancer activation. Distinct modes of S4 silencer action upon distinct enhancers thus unravel a pathway that restricts CD4 expression to helper-lineage cells by silencer-independent and Runx-dependent repression of maturation enhancer activity in cytotoxic-lineage cells.
Highlights
An intronic silencer, S4, in the Cd4 gene has been shown to be responsible for the helperlineage-specific expression of CD4; S4 requires Runx complex binding to exert its silencer function against the enhancer-mediated Cd4 activation by modulating the epigenetic state of the Cd4 gene
Post-selection thymocytes expressing major histocompatibility complex (MHC)-class I (MHC-I) restricted T-cell antigen receptor (TCR) are specified to differentiate into the cytotoxic-lineage and acquire CD4−CD8+ single-positive (SP) phenotype by terminating CD4 expression, whereas MHC-class II (MHC-II)-mediated TCR engagement generates CD4+CD8− SP thymocytes committed to the helper-lineage by inhibiting CD8 expression
To examine whether the activity that induces DNA demethylation in the Cd4 locus is specific to E4p, we tested how a heterologous enhancer behaves in the Cd4 locus
Summary
S4, in the Cd4 gene has been shown to be responsible for the helperlineage-specific expression of CD4; S4 requires Runx complex binding to exert its silencer function against the enhancer-mediated Cd4 activation by modulating the epigenetic state of the Cd4 gene. Post-selection thymocytes expressing MHC-class I (MHC-I) restricted TCRs are specified to differentiate into the cytotoxic-lineage and acquire CD4−CD8+ single-positive (SP) phenotype by terminating CD4 expression, whereas MHC-class II (MHC-II)-mediated TCR engagement generates CD4+CD8− SP thymocytes committed to the helper-lineage by inhibiting CD8 expression. Such stage-specific and lineage-specific expression of CD4/CD8 co-receptors is regulated at the transcriptional level by a combinational regulation of cis-regulatory elements[2]. Our results reveal that Runx complexes repress two enhancers, E4p and E4m, in distinct manners, providing a novel insight that revises a silencer-based model for a lineage-specific Cd4 expression
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