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It belongs to the zinc finger protein of the cerebellum (Zic) family of genes that share a C2H2-type zinc finger domain, similar to the <jats:italic>GLI<\/jats:italic> family of genes. In order to clarify the role of Zic2 in gene regulation, we searched for its direct target genes using chromatin immunoprecipitation (ChIP). We identified <jats:italic>TGIF1<\/jats:italic> (HPE4), another holoprosencephaly-causative gene in humans. We identified Zic2-binding sites (ZBS) on the 5\u2032 flanking region of <jats:italic>Tgif1<\/jats:italic> by <jats:italic>in vitro<\/jats:italic> DNA binding assays. ZBS were essential for Zic2-dependent transcriptional activation in reporter gene assays. Zic2 showed a higher affinity to ZBS than GLI-binding sequences. Zic2-binding to the cis-regulatory element near the <jats:italic>Tgif1<\/jats:italic> promoter may be involved in the mechanism underlying forebrain development and incidences of HPE.<\/jats:p>","DOI":"10.1038\/s41598-018-20242-2","type":"journal-article","created":{"date-parts":[[2018,1,26]],"date-time":"2018-01-26T13:02:20Z","timestamp":1516971740000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Link between the causative genes of holoprosencephaly: Zic2 directly regulates Tgif1 expression"],"prefix":"10.1038","volume":"8","author":[{"given":"Akira","family":"Ishiguro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Hatayama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maky I.","family":"Otsuka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Aruga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,2,1]]},"reference":[{"key":"20242_CR1","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1172\/JCI38937","volume":"119","author":"X Geng","year":"2009","unstructured":"Geng, X. & Oliver, G. 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