Integrative genomic analyses of WNT11: Transcriptional mechanisms based on canonical WNT signals and GATA transcription factors

Abstract

We and others previously cloned and characterized vertebrate WNT11 orthologs, which are involved in gastrulation, neurulation, cardiogenesis, nephrogenesis, and chondrogenesis during fetal development. WNT11 orthologs activate both canonical and non-canonical WNT signaling cascades depending on the expression profile of WNT receptors, such as Frizzled family members, LRP6, ROR2, and RYK. Human WNT11 is expressed in breast cancer, gastric cancer, esophageal cancer, colorectal cancer, neuroblastoma, Ewing sarcoma, and prostate cancer. Canonical WNT signals and GATA family members are involved in WNT11 transcription during embryogenesis of model animals; however, precise mechanisms of WNT11 expression remain unclear. Here, refined integrative genomic analyses of WNT11 are carried out to elucidate the mechanisms of WNT11 transcription. The WNT11 gene was found to encode two isoforms by using alternative first exons. WNT11 isoform A (NM_004626.2 RefSeq) consists of exons 2, 3, 4, 5 and 6, whereas WNT11 isoform B consists of exons 1, 2, 3, 4, 5 and 6. We identified double TCF/LEFbinding sites within the proximal promoter regions (-48-bp position from the TSS of human WNT11 isoform B and -43-bp position from the TSS of human WNT11 isoform A), and also double GATA-binding sites within intron 2 of human WNT11 gene (+933-bp and +5001-bp positions from TSS of human WNT11 isoform A). Double TCF/LEF- and double GATAbinding sites within the regulatory regions of human WNT11 gene were conserved in other mammalian WNT11 orthologs. These facts indicate that canonical WNT signals and GATA family members directly upregulate WNT11 transcription. Canonical WNT-induced WNT11 activates non-canonical WNT signaling cascades to induce cellular movement, and also activates the Ca2+-MAP3K7-NLK signaling cascade to break the canonical WNT signaling. Canonical WNT-to-WNT11 signaling loop is involved in cellular migration during embryogenesis as well as tumor invasion during carcinogenesis.