Paxillin-dependent regulation of IGF2/H19 gene cluster expression

Paxillin (PXN) is a focal adhesion protein implicated in signal transduction from the extracellular matrix. Recently, it has been shown to shuttle between the cytoplasm and the nucleus. When inside the nucleus, paxillin promotes cell proliferation. Here, we introduce paxillin as a transcriptional regulator of IGF2 and H19 genes. It does not affect the allelic expression of the two genes; rather, it regulates long-range chromosomal interactions between IGF2 or H19 promoter and a shared distal enhacer on an active allele. Specifically, paxillin stimulates the interaction between the enhancer and the IGF2 promoter, thus activating IGF2 gene transcription, while it restrains the interaction between the enhancer and the H19 promoter, downregulating the H19 gene. We found that paxillin interacts with cohesin and Mediator which have been shown to mediate long-range chromosomal looping. We propose that these interactions occur at the IGF2/H19 gene cluster and are involved in the formation of loops between the IGF2/H19 promoters and the enhacer, and thus the expression of corresponding genes. These observations contribute to a mechanistic explanation of paxillin ́s role in proliferation and fetal development. Jo ur na l o f C el l S ci en ce A cc ep te d m an us cr ip t