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motif A/GGGAA through their N-terminal zinc-finger domain.5,6 Furthermore, all IKAROS family members har- bor two additional C-terminal zinc-fingers required for homo- and heterodimerization between the different IKZF proteins (Figure 1A). The formation of homo- or het- erodimers between IKAROS zinc-finger proteins with a functional DNA binding domain strongly enhances their DNA affinity and transcriptional activity. However, a common feature of IKZF1 and related family members is the presence of shorter variants due to alternative splicing. These variants often lack DNA binding activity but retain the ability to interact with full-length IKZF1-IKZF5, there- by creating dominant-negative isoforms. A well-known splice variant of both the mouse and human IKZF1 gene is the IK6 isoform, which lacks exons 4 to 7 that encode the four N-terminal zinc-fingers representing the DNA bind- ing domain (Figure 1B).
IKZF1 mainly regulates gene expression through associ- ation with the nucleosome remodeling and deacetylase complex,7-10 which includes histone deacetylases HDAC1, HDAC2 and the ATP-dependent chromatin remodeling proteins CHD3 and CHD4. The nucleosome remodeling and deacetylase complex is involved in both transcription- al repression as well as gene activation by IKZF1.11,12 Gene silencing by IKZF1 is also facilitated through interaction
A
with Polycomb repressive complex 2, which promotes histone H3 lysine 27 trimethylation to maintain genes in an inactive state.13,14 Other transcriptional co-factors that can associate with IKZF1 and mediate gene regulation include CtBP, CtIP and SWI/SNF-related complex.15-17 On the other hand, IKZF1 may itself participate in transcrip- tion initiation through direct interactions with the general transcription factors TFIIB and TBP.16 IKZF1 also controls transcription elongation via association with protein phos- phatase 1α and cyclin-dependent kinase 9 (CDK9), the enzymatic component of the positive transcription elon- gation factor b.18-20 IKZF1-mediated transfer of protein phosphatase 1α to CDK9 promotes activation of positive transcription elongation factor b and recruitment to gene regulatory regions, thereby facilitating transcription elon- gation of IKZF1-target genes in hematopoietic cells.18
Distinct post-translational modifications are able to modify the function of IKZF1. Phosphorylation of IKZF1 at multiple serine and threonine residues by casein kinase II impairs its function as a transcription factor.20-22 Conversely, casein kinase II inhibition enhances the tran- scriptional repressor function of IKZF1.23 On the other hand, dual-specificity kinases BTK and SYK both phos- phorylate IKZF1 on specific serine residues in close prox- imity of the DNA binding domain to augment its nuclear
B
Figure 1. Overview of the human family of IKAROS zinc-finger (IKZF) transcription factors and IKZF1 isoforms. (A) Schematic representa- tion of the five IKZF proteins (IKZF1-IKZF5), including the N-terminal zinc-fingers that define the DNA-binding domain and the two C-terminal zinc-fingers representing the dimerization domain. The colored boxes indicate the individ- ual regions within the protein that are encoded by distinct exons. (B) The common IKZF1 splice variants (IK1-IK8) are shown, including the short- er isoforms that are generated by alternative splicing. The splice variants lacking exons 4 and 5 (IK6-IK8) represent dominant-negative iso- forms of IKZF1.
haematologica | 2018; 103(4)