Zinc-finger proteins in health and disease

Abstract

Zinc-finger proteins (ZNFs) are one of the most abundant groups of proteins and have a wide range of molecular functions. Given the wide variety of zinc-finger domains, ZNFs are able to interact with DNA, RNA, PAR (poly-ADP-ribose) and other proteins. Thus, ZNFs are involved in the regulation of several cellular processes. In fact, ZNFs are implicated in transcriptional regulation, ubiquitin-mediated protein degradation, signal transduction, actin targeting, DNA repair, cell migration, and numerous other processes. The aim of this review is to provide a comprehensive summary of the current state of knowledge of this class of proteins. Firstly, we describe the actual classification of ZNFs, their structure and functions. Secondly, we focus on the biological role of ZNFs in the development of organisms under normal physiological and pathological conditions.

Figure 1

Structure, molecular functions, and subcellular localization of ZNFs. (a) A schematic representation of the structure of C2H2, RING, PHD, and LIM zinc-finger domains. (b) A schematic representation of the structure of some ZNFs with multiple zinc-finger domains. (c) Gene ontology analysis of 1723 annotated ZNFs according to molecular function, log₁₀(P-val)<(−5). (d) Schematic representation of the subcellular localization of different ZNFs.

Figure 2

Molecular pathways regulated by ZNFs in physiological conditions. (a) ZNF750 regulates keratinocytes terminal differentiation by interacting with KLF4 and chromatin regulators. This interaction leads to the positive regulation of genes (PPL, PKP1) involved in differentiation. In addition, ZNF750 interacts with KDM1A and negatively regulates progenitor gene expression (RBBP8, HOMER3). ZNF750 directly regulates the expression of KLF4, which subsequently modulates the expression of the indicated genes. (b) KLF4 regulates epithelial cell differentiation by interacting with β-catenin and repressing the WNT signalling pathway. (c) KLF5 is involved in myoblast differentiation, acting as a co-factor for MyoD. This action leads to the upregulation of the indicated genes. (d) The presence of SLUG on the PPARG promoter reduces HDAC1 recruitment, leading to C/EBP-mediated activation of PPARG expression. This effect promotes adipogenesis.

Figure 3

Molecular mechanisms underlying the role of ZNFs in cancer biology (a) ZNF185 interacts with actin filaments in focal adhesion sites to regulate migration and invasion. (b) TGF-β induces the expression of ZEB1, which represses CDH1 expression, hence inducing EMT. (c) ZNF281 regulates expression of genes involved in the DDR and EMT. (d) ZNF750 acts as tumour suppressor gene by inducing the expression of the lncRNA TINCR, which inhibits cancer cell proliferation. In addition, ZNF750 represses LAMC2 expression, inhibiting cancer cell migration. (e) ZBP89 represses VIM and ODC1 expression by recruiting HDAC1 to the promoters of these genes. Moreover, ZBP89 induces MMP3 expression. (f) MDM2 interacts with p53 to induce proteasomal degradation and impair p53 to exert its function.

Figure 4

Transcriptional regulation of some ZNFs transcription and their roles in cancer. (a) SNAIL promotes the EMT by positively regulating the expression of ZNF281 and negatively regulating the expression of the tumour suppressor miR-34a. (b) p63 induces ZNF750 expression, which subsequently represses cell proliferation and migration. (c) ZNF185 expression is regulated by Brg-1 and the SWI/SNF complex. Its activation represses cell invasion and tumour growth. (d) TCF/ β-catenin induces ZBP89 expression, promoting tumour growth and metastasis.

Figure 5

Regulation of ZNFs target genes in human diseases. (a) ZNF746 represses the expression of PGC-1α, resulting in the loss of dopaminergic neurons in the substantia nigra of Parkinson’s patients. (b) ZNF750 regulates the expression of epidermal differentiation markers, such as FLG, LOR, SPINK5, ALOX12B, and DSG, which are altered in human skin diseases. (c) Glis1 regulates transcription of several genes involved in the differentiation of epidermal keratinocytes, including cornifin, involucrin, and transglutaminase 1. The expression of these genes is altered in psoriasis. (d) Glis3 modulates expression of the insulin gene, contributing to the pathogenesis of neonatal diabetes and hypothyroidism. (e) Troponin C and I and myosin light chain-3 genes are induced during cardiac hypertrophy due to overexpression of the GATA4 transcription factor. (f) The expression of SEMA3C and its receptor PLXNA2 is downregulated by GATA6 mutations, resulting in the development of OFT defects associated with CHDs.