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miR290-5p and miR292-5p Activate the Immunoglobulin kappa Locus

  • Author(s): Garcia, Patty Bertha
  • Advisor(s): Schlissel, Mark S
  • et al.
Abstract

Regulated expression of miRNAs influences development in a wide variety of contexts. We report here that miR290-5p and miR292-5p are induced at the pre-B stage of murine B cell development and that they influence assembly of the Igκ light chain gene by contributing to the activation of germline Igκ transcription (κGT). We found that upon forced over-expression of miR290-5p/292-5p in Abelson Murine Leukemia Virus (AMuLV) transformed pro-B cells two known activators of κGT, E2A and NF-κB, show increased DNA binding activity. E2A shows increased binding specific to the kappa intronic enhancer in vivo. Conversely, knockdown of miR290-5p/292-5p in AMuLV pro-B cells blunted drug-induced activation of κGT. Furthermore, miR290-5p/292-5p knockdown also blunted κGT activation, but not Rag1/2 expression, in an IL-7 dependent primary pro-B cell culture system. In addition, we identified a deficiency in κGT induction in miR290 cluster knockout mice. We hypothesize that increased expression of miR290-5p and miR292-5p contributes to the induction of κGT at the pre-B stage of B cell development through increased DNA binding activity of NF-κB and E2A and to kappa locus regulatory sequences. To identify the pathway(s) through which miR290-5p/292-5p are acting, we observed that inhibitors of both NF-κB and E2A, IκBα and Id2 respectively are indirectly regulated. In attempts to identify the direct targets of miR290-5p/292-5p we found that Pim1 and Blimp1 may be direct targets. In addition, miR290-5p/292-5p regulation of Blimp1 differs in a cell-context dependent manner. In conclusion, we report here that miR290-5p and miR292-5p play a role in regulating B cell developmental pathways at the pre-B stage.

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