Systematized reporter assays reveal ZIC protein regulatory abilities are Subclass-specific and dependent upon transcription factor binding site context

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 -repre...

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Bibliographic Details
Published in:Scientific reports 2020-08, Vol.10 (1), p.13130-13130, Article 13130
Main Authors: Ahmed, Jehangir N., Diamand, Koula E. M., Bellchambers, Helen M., Arkell, Ruth M.
Format: Article
Language:English
Subjects:
631/208/191
631/208/191/1908
631/208/2490
631/337/572
631/45/612/1229
631/45/612/822
Binding sites
Cell activation
Deoxyribonucleic acid
DNA
Gene Expression Regulation
Genes, Reporter
Genomes
HEK293 Cells
Humanities and Social Sciences
Humans
multidisciplinary
Pathogenicity
Pathogens
Proteins
Response Elements
Science
Science (multidisciplinary)
Transcription factors
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
Zinc finger proteins
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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. 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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-020-69917-9