Changing Faces of Transcriptional Regulation Reflected by Zic3

Abstract

The advent of genomics in the study of developmental mechanisms has brought a trove of information on gene datasets and regulation during development, where the Zic family of zinc-finger proteins plays an important role. Genomic analysis of the modes of action of Zic3 in pluripotent cells demonstrated its requirement for maintenance of stem cells pluripotency upon binding to the proximal regulatory regions (promoters) of genes associated with cell pluripotency (Nanog, Sox2, Oct4, etc.) as well as cell cycle, proliferation, oncogenesis and early embryogenesis. In contrast, during gastrulation and neurulation Zic3 acts by binding the distal regulatory regions (enhancers, etc) associated with control of gene transcription in the Nodal and Wnt signaling pathways, including genes that act to break body symmetry. This illustrates a general role of Zic3 as a transcriptional regulator that acts not only alone, but in many instances in conjunction with other transcription factors. The latter is done by binding to adjacent sites in the context of multi-transcription factor complexes associated with regulatory elements.

Keywords: Enhancer; Gastrulation; Left-right asymmetry; Neurogenesis; Promoter; Stem cells; Transcription; Zebrafish..

Fig. (1)

The pairwise arrangement of zic genes in the zebrafish genome. An additional zic gene in zebrafish, zic6, is located in pair with zic3 on chromosome 14. Although zic6 has been lost in higher vertebrates, the fragment of chromosome 14 containing zic3 retains the syntenic relationship with that of the human X-chromosome

Fig. (2)

Proposed model of Zic3 regulatory mechanism. In pluripotent ES cells, Zic3 is likely to act as a general TF, binding to basal transcriptional elements near the promoter of pluripotency genes. In the developing embryo, Zic3 binds mainly to distal enhancer elements to regulate tissue-specific expression of target genes. The binding to different enhancer elements is regulated spatiotemporally through epigenetic mechanisms or recruitment by different binding partners represented by grey colored shapes.

Fig. (3)

Summary of the multiple roles of Zic3 in different spatiotemporal contexts in pluripotent cells and during zebrafish development. Expression of zic3 is indicated with red shade. Functions of Zic3 within a specific expression domain, as well as the relevant downstream target genes (direct and indirect) are denoted in colored boxes.