title: Paxillin-dependent regulation of IGF2 and H19 gene cluster expression.
abstract: Paxillin (PXN) is a focal adhesion protein that has been 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 the IGF2 or H19 promoter and a shared distal enhancer on an active allele. Specifically, paxillin stimulates the interaction between the enhancer and the IGF2 promoter, thus activating IGF2 gene transcription, whereas it restrains the interaction between the enhancer and the H19 promoter, downregulating the H19 gene. We found that paxillin interacts with cohesin and the mediator complex, which have been shown to mediate long-range chromosomal looping. We propose that these interactions occur at the IGF2 and H19 gene cluster and are involved in the formation of loops between the IGF2 and H19 promoters and the enhancer, and thus the expression of the corresponding genes. These observations contribute to a mechanistic explanation of the role of paxillin in proliferation and fetal development.
authors.affiliation: Department of Biology of the Cell Nucleus, Institute of Molecular Genetics AS CR, Prague 142 20, Czech Republic Faculty of Science, Charles University in Prague, Prague 128 43, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Marášek
authors.affiliation: Department of Biology of the Cell Nucleus, Institute of Molecular Genetics AS CR, Prague 142 20, Czech Republic Department of Genome Integrity, Institute of Molecular Genetics AS CR, Prague 142 20, Czech Republic.
authors.forename: Rastislav
authors.initials: R
authors.lastname: Dzijak
authors.affiliation: Department of Biology of the Cell Nucleus, Institute of Molecular Genetics AS CR, Prague 142 20, Czech Republic.
authors.forename: Irina
authors.initials: I
authors.lastname: Studenyak
authors.affiliation: Department of Biology of the Cell Nucleus, Institute of Molecular Genetics AS CR, Prague 142 20, Czech Republic.
authors.forename: Jindřiška
authors.initials: J
authors.lastname: Fišerová
authors.affiliation: Department of Biology of the Cell Nucleus, Institute of Molecular Genetics AS CR, Prague 142 20, Czech Republic.
authors.forename: Lívia
authors.initials: L
authors.lastname: Uličná
authors.affiliation: Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology AS CR, Prague 142 00, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Novák
authors.affiliation: Department of Biology of the Cell Nucleus, Institute of Molecular Genetics AS CR, Prague 142 20, Czech Republic hozak@img.cas.cz.
authors.forename: Pavel
authors.initials: P
authors.lastname: Hozák
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004742:Enhancer Elements, Genetic; D005109:Extracellular Matrix / Q000235:genetics; D047109:Fetal Development / Q000235:genetics*; D022001:Focal Adhesions / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics; D051419:Paxillin / Q000008:administration & dosage*; D011401:Promoter Regions, Genetic; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000097722:Cohesins
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D007335:Insulin-Like Growth Factor II; D051419:Paxillin; D062085:RNA, Long Noncoding; D000097722:Cohesins; C094335:H19 long non-coding RNA; C035170:IGF2 protein, human
keywords: Cohesin; Enhancer; H19; IGF2; Imprinting; Paxillin