Identification of Sall2 isoform-specific target genes in response to Doxorubicin

Gene expression is regulated in part by transcription factors which form one of the most important mechanisms regulating the differentiation, development and cellular homeostasis. A transcription factor, called Sall2, member of the Spalt-sal genes involved in normal development, has not been well characterized, with little information available about its regulation and specific targets. Recently, mutations in Sall2 have been associated with genetic diseases such as ocular coloboma and Alport syndrome. Moreover, there are now more evidence to suggest that Sall2 has an important role in cancer. Like, as Sall2 expression is deregulated in various cancers including synovial sarcoma, Wilm's tumor, ovarian cancer, testicular cancer and others. Several studies, including our data, suggest that Sall2 is a tumor suppressor. However, this suppressor function remains controversial. Because, Sall2 is increased in some cancers, Sall2 Knockout's mice show no spontaneous tumor formation and recently Sall2 was identified as one of the four essential transcription factors for formation of glioblastoma, which together suggests a oncogenic role for Sall2. That's where we wonder "How could explain this controversy?". One way is, Sall2 gene contains two alternative promoters (P1 and P2), conserved between human and mouse and could form two Sall2 isoforms, called E1 and E1A. These isoforms differ only in the N-terminal domain. However, bioinformatic analysis of these domains predicts that Sall2 isoforms differ in their regulation and function. According to this assumption, it was shown that E1 isoform can interact with NuRD complex, but not E1A, that can act as a transcriptional repressor. In addition, unpublished data from our lab suggest that only the E1A isoform can induce transcription of the proapoptotic gene NOXA1. However, controversial roles proposed for Sall2 function in a normal and pathological state, that could be resolved through an understanding of expression, regulation, and function of Sall2 isoforms. Therefore, we propose that by using complementary approaches include stable modifying genome (genome editing) for Sall2 isoforms, ChIP-seq analysis, and bioinformatics analysis, identifying Sall2 isoform-specific target genes in normal and in response to genotoxic stress. Until now, I have 3 published paper in this area. In addition, there are 2 papers submitted in review.