Abstract
The ZIC proteins are a family of transcription regulators with a well-defined zinc finger DNA-binding domain and there is evidence that they elicit functional DNA binding at a ZIC DNA binding site. Little is known, however, regarding domains within ZIC proteins that confer trans-activation or -repression. To address this question, a new cell-based trans-activation assay system suitable for ZIC proteins in HEK293T cells was constructed. This identified two previously unannotated evolutionarily conserved regions of ZIC3 that are necessary for trans-activation. These domains are found in all Subclass A ZIC proteins, but not in the Subclass B proteins. Additionally, the Subclass B proteins fail to elicit functional binding at a multimerised ZIC DNA binding site. All ZIC proteins, however, exhibit functional binding when the ZIC DNA binding site is embedded in a multiple transcription factor locus derived from ZIC target genes in the mouse genome. This ability is due to several domains, some of which are found in all ZIC proteins, that exhibit context dependent trans-activation or -repression activity. This knowledge is valuable for assessing the likely pathogenicity of variant ZIC proteins associated with human disorders and for determining factors that influence functional transcription factor binding.
Highlights
The ZIC proteins are a family of transcription regulators with a well-defined zinc finger DNA-binding domain and there is evidence that they elicit functional DNA binding at a ZIC DNA binding site
Since a missense mutation affecting a key cysteine residue in the 4th zinc fingers (ZFs) of ZIC2, that causes the C370S amino acid substitution, eliminates DNA binding ability[15], an orthologous substitution was made in cDNAs encoding each of the four remaining human ZIC proteins (Fig. 1A)
The ZIC family of transcription factors are essential for multiple lineage decisions during embryonic development and recent work suggests they play important roles in stem cell function[21,28,29,30] and their dysregulations leads to cancer[31,32,33,34,35,36]
Summary
The ZIC proteins are a family of transcription regulators with a well-defined zinc finger DNA-binding domain and there is evidence that they elicit functional DNA binding at a ZIC DNA binding site. All ZIC proteins, exhibit functional binding when the ZIC DNA binding site is embedded in a multiple transcription factor locus derived from ZIC target genes in the mouse genome This ability is due to several domains, some of which are found in all ZIC proteins, that exhibit context dependent trans-activation or -repression activity. A corollary of the gene-pair arrangement is that Zic[1] and Zic[4] as well as Zic[2] and Zic[5] have extensive overlap in expression domains in multiple organisms[9,10,11,12,13] How these sequence differences influence the function of the distinct Subclass proteins is unknown. ZIC3 exhibits functional DNA binding, i.e. ZIC3 both binds DNA and elicits a transcriptional response
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