C2H2-Type Zinc Finger Proteins: Evolutionarily Old and New Partners of the Nuclear Hormone Receptors

Abstract

Nuclear hormone receptors (NRs) are evolutionarily conserved ligand-dependent transcription factors. They are essential for human life, mediating the actions of lipophilic molecules, such as steroid hormones and metabolites of fatty acid, cholesterol, and external toxic compounds. The C2H2-type zinc finger proteins (ZNFs) form the largest family of the transcription factors in humans and are characterized by multiple, tandemly arranged zinc fingers. Many of the C2H2-type ZNFs are conserved throughout evolution, suggesting their involvement in preserved biological activities, such as general transcriptional regulation and development/differentiation of organs/tissues observed in the early embryonic phase. However, some C2H2-type ZNFs, such as those with the Krüppel-associated box (KRAB) domain, appeared relatively late in evolution and have significantly increased family members in mammals including humans, possibly modulating their complicated transcriptional network and/or supporting the morphological development/functions specific to them. Such evolutional characteristics of the C2H2-type ZNFs indicate that these molecules influence the NR functions conserved through evolution, whereas some also adjust them to meet with specific needs of higher organisms. We review the interaction between NRs and C2H2-type ZNFs by focusing on some of the latter molecules.

C2H2-Type Zinc Finger Proteins in Brain Development, Neurodevelopmental, and Other Neuropsychiatric Disorders: Systematic Literature-Based Analysis

“…C 2 H 2 -ZNFs are found throughout the organisms from yeasts to humans, whereas their numbers have exponentially expanded following the species evolution, particularly in vertebrates including humans (33). Poly-ZNFs tend to present from lower to higher organisms and mediate the fundamental functions shared by most of them, such as embryonic/fetal development, organogenesis, and limb formation (21). On the other hand, KRAB-ZNFs and SCAN-ZNFs, which appeared in the animal kingdom from vertebrates and mammals, respectively, show their numbers have significantly expanded in higher organisms, with the former demonstrating this trend more obviously (33).…”

“…On the other hand, KRAB-ZNFs and SCAN-ZNFs, which appeared in the animal kingdom from vertebrates and mammals, respectively, show their numbers have significantly expanded in higher organisms, with the former demonstrating this trend more obviously (33). It is likely that the addition of these domains to C 2 H 2 -ZNFs, particularly the KRAB domain, appears to be required for supporting the functions specific to higher organisms, for example, sophisticated cognitive functions unique to humans (21). These pieces of evolutionary evidence on C 2 H 2 -ZNFs may explain our successful identification of specific C 2 H 2 -ZNF subtypes in particular forms of NDDs.…”

“…C 2 H 2 -ZNFs form the largest TF family in the animal kingdom with significant expansion of their members through species evolution (20). The family consists of ∼800 members in humans (20,21). In addition to C 2 H 2 -type zinc fingers (ZFs), these proteins contain other functional domains, such as BTB (BR-C, ttk, and bab)/POZ (Pox virus and Zinc finger), KRAB (Krüppel-associated box), and/or SCAN (SRE-ZBP, CTfin51, AW-1, and Number 18 cDNA), and are classified into four subtypes depending on the possession of these domains: (1) poly-ZNFs without any other domains, (2) BTB/POZ-ZNFs, (3) KRAB-ZNFs, and (4) SCAN-ZNFs (20,21) (Figure 1).…”

“…Among the functional domains of C 2 H 2 -type ZNFs, BTB/POZ, and KRAB domains have transcriptional regulatory activity (mainly repressive but sometimes enhancing) by attracting various repressive cofactor molecules, such as the histone deacetylases, corepressor complex, heterochromatin protein 1 (HP1), and/or the KRAB-associated protein-1 (KAP1). In contrast, the SCAN domain does not have such activities (21,32). About seven percent (%) of the human C 2 H 2 -type ZNFs have a BTB/POZ domain, while 43% harbor a KRAB domain and 7% contain a SCAN domain (33).…”

“…One ZNF536 polymorphism (rs77554113) is correlated with remission rates of MDD patients who are under antidepressant treatment, indicating its potential roles in MDDrelated pathophysiologic processes (166). ZNF536 is a poly-ZNF highly expressed in neuronal cells and known to suppress neuronal differentiation (21,63).…”