Role of Zic Family Proteins in Transcriptional Regulation and Chromatin Remodeling

Abstract

Proper functions of Zic proteins are essential for animals in health and disease. Here, we summarize our current understanding of the molecular properties and functions of the Zic family across animal species and paralog subtypes. Zics are basic proteins with some posttranslational modifications and can move to the cell nucleus via importin- and CRM1-based nucleocytoplasmic shuttling mechanisms. Degradation is mediated by the ubiquitin proteasome system. Many Zic proteins are capable of binding to two types of target DNA sequences (CTGCTG-core-type and GC-stretch-type). Recent chromatin immunoprecipitation assays showed that CTGCTG-core-type target sequences are enriched in enhancers. Nonetheless, the DNA binding is not always required for transcriptional regulation by Zic proteins. On the other hand, Zic proteins bind many proteins including transcription factors (Gli1-3, Tcf1 or Tcf4, Smad2 or Smad3, Oct4, Pax3, Cdx, and SRF), chromatin-remodeling factors (NuRD and NURF), and other nuclear enzymes (DNA-PK, PARP1, and RNA helicase A). Zic family-mediated gene expression control involves both their actions near the transcription start site and those affecting the global gene expression via binding to enhancers. Although Zic proteins perform essential functions in transcriptional regulation of Oct4 and Nanog expression via their promoters, recent genome-wide analyses of the Zic-binding sites and their downstream targets indicate that Zic proteins are associated with distant regulatory elements and are the critical enhancer-priming nuclear regulators in organismal development. Chromatin-remodeling complexes such as NuRD and NURF that interact with Zic proteins have been shown to participate in Zic-mediated enhancer regulation.

ZIC3 Controls the Transition from Naive to Primed Pluripotency

“…ZIC transcription factors can bind similar DNA binding motifs ( Badis et al., 2009 ; reviewed in Hatayama and Aruga, 2018 ) and hence there is the potential for further cross talk between these factors at the level of chromatin binding. As ZIC3 exhibits transient activation kinetics, and ZIC2/5 expression is maintained at later stages, it is possible that some of the functions of ZIC3 are maintained and/or expanded by these factors as EpiLCs differentiate further.…”

A forebrain undivided: Unleashing model organisms to solve the mysteries of holoprosencephaly

“…Zic2 is the next most common gene, after Hh pathway components, to be disrupted in patients with HPE, and is unique among HPE genes in that most of the mutations arise de novo . Zic genes share common ancestry with the Gli gene family, as their DNA binding domains have been conserved during metazoan evolution . Telencephalic expression of Zic2 is induced by FGF and Wnt, and Zic2 functions to repress transcription of Fgf8 and Six3 in the zebrafish forebrain .…”

“…[39][40][41] Zic genes share common ancestry with the Gli gene family, as their DNA binding domains have been conserved during metazoan evolution. 42,43 Telencephalic expression of Zic2 is induced by FGF and Wnt, and Zic2 functions to repress transcription of Fgf8 and Six3 in the zebrafish forebrain. 44,45 In other cellular contexts, Zic2 inhibits canonical Wnt signaling through direct interaction with TCFs, 46,47 and controls Nodal signaling by means of a direct interaction with Smad2/3.…”

Upregulation of circ_0000069 stimulates cervical cancer development by enhancing proliferation, migration, invasion while inhibiting apoptosis through the miR-4429/ZIC2 axis

“…Zinc finger protein of the cerebellum 2 (ZIC2), transcription factors, was a member of ZIC family, involving in vertebrate development [12], oncogenesis [13], and transcriptional regulation [14].…”