A Developmentally Controlled Competitive STAT5-PU.1 DNA Binding Mechanism Regulates Activity of the Ig kappa E3 %26apos; Enhancer

作者：Hodawadekar Suchita; Park Kyoungsook; Farrar Michael A; Atchison Michael L^*

来源：The Journal of Immunology, 2012, 188(5): 2276-U647.

DOI：10.4049/jimmunol.1102239

Stage-specific rearrangement of Ig H and L chain genes poses an enigma because both processes use the same recombinatorial machinery, but the H chain locus is accessible at the pro-B cell stage, whereas the L chain loci become accessible at the pre-B cell stage. Transcription factor STAT5 is a positive-acting factor for rearrangement of distal V-H genes, but attenuation of IL-7 signaling and loss of activated STAT5 at the pre-B cell stage corresponds with Ig kappa locus accessibility and rearrangement, suggesting that STAT5 plays an inhibitory role at this locus. Indeed, loss of IL-7 signaling correlates with increased activity at the Ig kappa intron enhancer. However, the kappa E3%26apos; enhancer must also be regulated as this enhancer plays a role in Igk rearrangement. We show in this study that STAT5 can repress kappa E3%26apos; enhancer activity. We find that STAT5 binds to a site that overlaps the kappa E3%26apos; PU.1 binding site. We observed reciprocal binding by STAT5 and PU.1 to the kappa E3%26apos; enhancer in primary bone marrow cells, STAT5 and PU.1 retrovirally transduced pro-B cell lines, or embryonic stem cells induced to differentiate into B lineage cells. Binding by STAT5 corresponded with low occupancy of other enhancer binding proteins, whereas PU.1 binding corresponded with recruitment of IRF4 and E2A to the kappa E3%26apos; enhancer. We also find that IRF4 expression can override the repressive activity of STAT5. We propose a novel PU.1/STAT5 displacement model during B cell development, and this, coupled with increased IRF4 and E2A activity, regulates kappa E3%26apos; enhancer function. The Journal of Immunology, 2012, 188: 2276-2284.

• 出版日期2012-3-1