Transcription Factors of the NF1 Family: Possible Mechanisms of Inducible Gene Expression in the Evolutionary Lineage of Multicellular Animals E

ISSN 0022-0930, Journal of Evolutionary Biochemistry and Physiology, 2017, Vol. 53, No. 2, pp. 85—92. © Pleiades Publishing, Ltd., 2017. Original Russian Text © E.V. Romanovskaya, M.V. Vikhnina, T.V. Grishina, M.P. Ivanov, L.E. Leonova, E.V. Tsvetkova, 2017, published in Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, 2017, Vol. 53, No. 2, pp. 77—83.

REVIEWS

Transcription Factors of the NF1 Family: Possible Mechanisms of Inducible Gene Expression in the Evolutionary Lineage of Multicellular Animals E. V. Romanovskaya*, M. V. Vikhnina, T. V. Grishina, M. P. Ivanov, L. E. Leonova, and E. V. Tsvetkova St. Petersburg State University, St. Petersburg, Russia * e-mail: [email protected] Received September 1, 2016

Abstract—The review discusses the role of omnipresent transcription factors of the NF1 family in the development, establishment and regulation of tissue-specific gene expression in multicellular organisms with a different degree of complexity. The molecular mechanisms underlying the effect of these transcription factors on the development of tissues in the evolutionary lineage of multicellular animals are analyzed. DOI: 10.1134/S123456781702001X Key words: transcription factors, evolution, tissue-specific gene expression.

INTRODUCTION role of omnipresent transcription factors of the NF1 family in the development, establishment It is commonly accepted that the interaction of and regulation of tissue-specific gene expression transcription factors with their specific sequences in multicellular organisms with a different degree plays a key role in gene expression. A plenty of of complexity. transcription factors are involved in the develop- NF1 transcription factors (nuclear factor 1, also ment of multicellular organisms, including those known as CCAAT box-binding transcription fac- that begin to act at the earliest developmental tor, CTF) is a family of ubiquitous nuclear tran- stages [1] and participate in the establishment of scription factors, which specifically bind as dimers tissues-specific gene expression. Currently, the to the palindromic consensus DNA sequence quantitative characteristics and combinatorics of 5’-TGGCANNNTGCCA-3’ [6]. They were first binding these transcription factors are being hotly isolated from HeLa cells as factors stimulating discussed in the literature in terms of their contri- adenovirus HAdV-2 replication [7]. NF1 gene bution to the evolution of multicellular organisms, sequences were found almost in all taxa, from vi- own evolutionary changeability, and distribution ruses to mammals. The nf1 gene was revealed in across different taxa [2–5]. However, the mo- genomes of many invertebrates, for example, in lecular mechanisms underlying the interaction of Drosophila sp., Caenorhabditis elegans and Cae- transcription factors with DNA sequences remain norhabditis briggsae [8] as well as in the malaria unresolved. In the resent review, we consider the mosquito Anopheles gambiae. It is hypothesized

85 86 ROMANOVSKAYA et al. that the lancelet nf1 gene is ancestral to the whole can be divided into two subdomains [18]. The first nf1 gene family in vertebrates. Interestingly, in- represents an α-helix able to nonspecifically bind creased diversity of the NF1 family proteins cor- DNA (residues 1 to 78). The second subdomain relates with complication of the organism’s struc- (residues 75 to 182) is responsible for dimerization tural organization. In bacteria, protists, fungi and and interaction with adenoviral DNA-polymerase. plants, no NF1 homologs were found [9]. In mam- This subdomain also shows a weak specific affinity mals, transcription factors of the NF1 family are for DNA. A study of the chicken NF1 transcrip- encoded by four different genes (nf1-a, -b, -c, and tion factors demonstrated that these factors can -x), while in other vertebrates they are represent- form homo- and heterodimers in vitro with dif- ed by paralogs. In mice, knockouts of individual ferent dimeric combinations sharing a similar or genes of this family led to dissimilar phenotypes, identical affinity for DNA, specificity and stability suggesting that different isoforms regulate differ- [19]. This is consistent with data on the homology ent genes [10]. of DNA binding between domains of NF1 tran- Structure of NF1 transcription factors. The mo- scription factors [20]. lecular weight of NF1 transcription factors var- NF1 transcription factors in invertebrates. As ies within a range of 30–65 kDa [11]. In all their aforesaid, in most vertebrates there are four iso- isoforms, the N-terminal domain represents a forms of NF1 transcription factors, whereas most conserved homologous domain responsible for invertebrates have only one. Possible functions of DNA binding, while the proline-rich C-terminal NF1 transcription factors in invertebrates were domain contains a regulatory sequence and var- analyzed in the nematode C. elegans [21]. 586 ies in different isoforms [12, 13]. Presumably, this NF1 binding sites were found in its genome, i.e. varying is achieved via alternative splicing. The by about 100 times more than expected. However, C-terminal domain is functional, mediating the a site occupancy study by means of chromatin im- effect of a transcription factor on transcription munoprecipitation showed that only 55 of the sites [14]. This domain is suggested to come to direct are bound to NF1in vivo. Thus, it can be assumed protein–protein interactions. For example, the that NF1 binding to their sites as well as the in- isoform NF1-C C-terminal domain was shown to volvement of these factors in the development of interact with histone H3 [15]. Possible protein– a multicellular organism require some additional protein interactions in the NF1 family will be con- factors interacting directly with NF1. Possible sidered below. mechanisms of the involvement of NF1 in estab- The highly conserved N-terminal domain con- lishing tissue-specific gene expression in verte- tains about 200 amino acid residues. Specifically, brates are considered below. it contains four conserved cysteine residues (from Involvement of NF1 transcription factors and their 2 to 5) essential for its DNA-binding activity [16]. isoforms in the regulation of tissue-specific gene ex- By means of site-specific mutagenesis, it was pression in vertebrates. The earliest studies of NF1/ shown that Cys-2, Cys-4 and Cys-5 are required CTF showed their ability to bind to promoter re- for covalent binding to DNA, while Cys-3 is regions of rat sarcoma hras genes and human alpha sponsible for oxidative inactivation of a protein. globin genes [22]. NF1 transcription factors were Presumably, the Cys-3 residue performs the same shown to be involved in embryogenesis of the cen- function as that of redox-sensitive cysteines in tral nervous system (CNS), specifically, in differ- other DNA-binding molecules. Oxidative inacti- entiation of glial and neuronal cells, cell traffick- vation plays an important role in the DNA-pro- ing across different CNS parts, and migration of tein interaction, considerably reducing the affinity neurons beyond its limits [23]. The NF1-A tran- of the transcription factor NF1 for DNA. Using scription factor gene is located on chromosome 1 site-specific mutagenesis, it was also shown that at position 1p31.2–p31.3 and consists of 11 exons DNA-binding activity of the transcription factor [24], while the protein amino acid sequence is NF1 can be modified by 5-nucleotide spacers be- 99% identical in chicken and rat. In man, NF1- cause such an insertion reduces binding affinity A is composed of 554 amino acids, and its DNA- [17]. The NF1 N-terminal DNA-binding domain binding domain contains 194 amino acids. NF1-A

JOURNAL OF EVOLUTIONARY BIOCHEMISTRY AND PHYSIOLOGY Vol. 53 No. 2 2017 TRANSCRIPTION FACTORS OF THE NF1 FAMILY 87 is expressed at a quite high level in all parts of the stages, NF1-X is the first among the other NF1 brain, with highest expression observed in the cer- isoforms to be expressed in the developing cor- ebellum and nucleus caudatus [25]. Expression of tex of the cerebral hemispheres, prevailing in its the NF1-A transcription factor gene is known to deeper parts [27]. Deletions in exons 6 and 7 of play an important role in the normal development the NF1-X gene lead to the development of hu- of the brain. In mice, NF1-A knockout caused hy- man Marshall–Smith syndrome [34] and in case drocephaly and significantly reduced the postnatal of complete gene deletion to Malan (Sotos-like) survival rate, probably due to impossible formation syndrome [35, 36]. Ns1-x gene knockout mice of heterodimers with the involvement of NF1-A. have hippocampal and other brain deformations, It was also found that NF1-A (1) controls the ini- allowing the conclusion that the transcription fac- tiation of gliogenesis in the spinal cord by inducing tor NF1-X is essential for normal embryogenesis the synthesis of glutamate-aspartate transporters of the brain. GLAST [26], (2) controls differentiation of telen- The gene encoding NF1-C, like the NF1-X cephalic progenitor cells through repression of the gene, is located on human chromosome 19 at po- Notch signaling pathway effector Hes1 [27], (3) sition 19p13.3 [10], and due to alternative splic- regulates proliferation of human polyomavirus JC ing yields four isoforms. NF1-C1 contains a full (JCV) [28]. NF1-A also shows high affinity for the set of exons, whereas NF1-C2 and NF1-C3 lack site adjacent to the gene S promoter of hepatitis exon 9. Besides, NF1-C3 lacks exon 3, while B virus [29]. Using a monohybrid system, it was NF1-C4 lacks exons 9 and 10. In man, there is an established that NF1-A2 can activate the CYP2A3 additional 5’-terminal exon. It is represented by gene element in epithelial cells of the olfactory two types, 1A and 1B, which occur, respectively, system [30]. in transcripts C2/C3 and C1/C4, allowing these The gene encoding the human transcription two transcript groups to be controlled by differ- factor NF1-B is located on chromosome 9 [10] ent promoters [37]. The transcription factor itself and contains 12 exons, while the protein consists consists of 502 amino acids [38]. Isoforms C1 and of 494 amino acids [31]. By now, it is known that C4 have the identical 5’ C-terminus, which differs alternative splicing can form three isoforms– from C-domains in isoforms C2 and C3. NF1-C NF1-B1, NF1-B2 and NF1-B3 [32]. Co-expres- displays no marked tissue specificity, although all sion of the isoform NF1-B3 with other isoforms of four isoforms are expressed in different tissues with the NF1-B, -C and -X families revealed a strong different intensity. The isoform NF1-C2 is most decrease in transcription activity as compared to widespread in human tissues, NF1-C1 and NF1- the independent action of these transcription fac- C3 are expressed to a lesser degree, while NF1-C4 tors. This is due to the fact that NF1-B3 decreases is the least occurring isoform [12]. The NF1-C2 the ability of the other NF1 proteins to bind to isoform is an important component of the tissue- DNA through the formation of heterodimers with specific activating complex, which encodes biliary them [32]. In mice, nf1-b knockout leads to mu- salt-dependent lipase in the murine milk [39]. It is tations in the hippocampus, indicating the role of interesting that the same isoform is also involved the isoform NF1-B, as well as the isoform NF1- in the regulation of expression of tumor suppres- A, in hippocampus development [33]. The genes sor p53 in vivo in the mouse mammary gland dur- encoding the proteins NF1-B and NF1-A were ing gestation [40]. Regulation of rat hormone- shown to be expressed at a high level in the ven- dependent tryptophan 2,3-dioxygenase is likely to tricular zone of the spinal cord at the very begin- depend on NF1 binding to specific sites located in ning of gliogenesis [25]. the DNase 1-sensitive regions [41, 42]. In man, the gene of the transcription factor Expression of the transcription factor NF1-C NF1-X is located on chromosome 19 and contains in murine and human odontoblasts plays an im- 11 exons [10]; there are 5 identified isoforms NF1- portant role in differentiation and proliferation of X, resulting from alternative splicing. NF1-X gene these cells as well as in the formation of molar root expression patterns appreciably overlap with those dentin [43]. of NF1-A and NF1-B. At early developmental Possible molecular mechanism underlying the ef-

JOURNAL OF EVOLUTIONARY BIOCHEMISTRY AND PHYSIOLOGY Vol. 53 No. 2 2017 88 ROMANOVSKAYA et al. fect of NF1 transcription factors. One of the most tionally competent structure, allowing thereby topical and realistic hypotheses concerns the in- other transcription factors to bind DNA [15]. teraction of NF1 factors with the chromatin ma- Besides, the interaction of NF1-C with yeast trix. The pertinent data obtained on model sys- histone H3 was characterized. Using a two-hybrid tems LTR MMTV and Xenopus laevis oocytes, assay, the hybrid protein GAL4, bound to the pro- specifically concerning the possible role of NF1 in line-rich NF1-C domain in mammalian cells, was reorganization of the chromatin structure, as well co-expressed with yeast hybrid histone H3 associ- as contradictions arising from the use of different ated with the activation domain of the herpes sim- model systems, are surveyed in detail by Chikh- plex virus protein VP16. Interaction of the hybrid irzhina et al. [44]. protein GalPRO with VP16-H3 led to enhanced Nucleosome structure prevents binding of dif- transcriptional activation due to strong activation ferent transcription factors to DNA unequally. activity of VP16. Co-expression of GalPRO asso- In such proteins as NF-kB and steroid hormone ciated with hybrid VP16 and the mammalian pro- receptors, the affinity for nucleosomal and free line-rich domain H3.3 caused strong expression DNA is almost the same. The factors TFIIA, HSP of the reporter promoter, supporting the specific and Sp1 bind to nucleosomal DNA by an order interaction of the NF1-C activation domain with weaker than to native DNA [45]. It was shown that histone H3. Other variant H3 forms, e.g. H3.2 and affinity of NF1 transcription factors to nucleoso- H3.1, do not interact with GalPRO, demonstrat- mal DNA is 100 times weaker than to free DNA ing a high interaction specificity. The fact that a [44], however, there is evidence that under certain sole variant of yeast histone H3 interacts with Gal- conditions the affinity of NF1 for DNA may rise. PRO can be explained by a structural similarity of For example, some DNA sequences may reduce H3 exactly to mammalian variant histone H3.3 the flexibility of a molecule, thus leading to the [15]. Specific interaction of NF1 with this histone attenuation of histone-DNA bonds. As a result, form agrees with its properties revealed during ge- the nucleosomal stability decreases and, accord- nomic analysis, namely, that the factor is located ingly, the affinity of transcription factors for DNA predominantly in the regulatory areas of actively increases [46]. The affinity of NF1 to DNA also expressing genes [49]. increases when DNA has only the H3–H4 histone Antisilencing activity of NF1 transcription factors. tetramer [47]. The investigated properties of NF1 suggest that Most plausible mechanism underlying the ac- NF1 provide potential activity of extended chro- tion of the factor NF1 implies the interaction of matin domains, being involved in demarcating its C-terminal domain with histones. The tran- chromatin functional domains. Constitutive telo- scription factor NF1-C was shown to interact dimeric heterochromatin is tightly associated with rectly with the mammalian histone H3.3 variant, silencing its genes, specifically with such histone however, no interaction was found with histones modifications as trimethylation of histone H3 ly- H1, H2A, H2B and H4 both in vivo and in vitro. sine 9 (H3K9Me3) or histone H4 lysine 20 (H4K- This was shown using a two-hybrid assay and co- 20Me3) [50]. Low activity of cellular demethyl- precipitation method. It was ascertained that in ases, able to remove methyl groups from telomeric the activation domain of the transcription factor loci, is consistent with the presence of these modi- there are two subdomains responsible for histone fications in constitutive heterochromatin. With H3.3 binding–one from amino acid residues 399 to allowance for the fact that activation domains of 438, another from residues 486 to 499. Mutations some transcription factors affect the range of in- in the DNA-binding domain, which disrupt the fluence of subtelomeric heterochromatin, the role interaction with DNA, did not affect the function of the factor NF1-C in providing antisilencing ac- of the transactivation domain [14]. Since the vari- tivity was analyzed [51, 52]. Using a two-hybrid ant H3.3 form is characteristic of active chromatin assay, the effect of the transcription factor NF1- [48], histone-binding activity of the C-terminal C subdomains, involved in binding histone H3.3, domain implies that transcription factors NF1 may on the spreading of silent telomeric chromatin initiate the release of chromatin into a transcrip- was studied. Chimeric proteins containing DNA-

JOURNAL OF EVOLUTIONARY BIOCHEMISTRY AND PHYSIOLOGY Vol. 53 No. 2 2017 TRANSCRIPTION FACTORS OF THE NF1 FAMILY 89 binding domain Gal4p, activation domain NF1- complex. After the recruitment of the SIR com- C and its functional subdomains were expressed plex, histone H3 and H4 tails undergo deacety- in yeast cells with the gene URA3 integrated into lation. The transcription factor NF1 binds to his- the telomeric locus VII-7. It was shown that full- tone H3 and modifies the subtelomeric chromatin length NF1-C and its activation domain (pro- structure. As a result of this, the SIR complex fails line-rich, PRD) display an antisilencing activity to bind and deacetylate histone H3. It is suggested in cells with its binding site located between the that it is exactly this interaction that arrests the URA transgene and telomeric region. The histone spreading of silent chromatin [56]. H3.3-binding subdomain, which includes the activation domain region (amino acid residues 486 CONCLUSION to 499), displays an antisliencing activity approxi- mating that of the full-length activation domain. An analysis of the literature data shows that The subdomain 399–438 also displays an antis- NF1 transcription factors are involved in the de- liencing activity, but to a lesser extent. A study of velopment of multicellular organisms with dis- pinpoint mutations in the subdomain 486–499 similar degree of complexity (from nematodes to showed that mutations at positions 397 and 491, humans) and establishing tissue-specific gene ex- reducing the efficiency of histone binding, also pression, as also supported by constantly appear- sharply reduce antisilencing activity of the activa- ing new data on the implication of NF1 in these tion domain. A study of the effect of NF-C on si- processes, for example, in sulfide-dependent lent transgene activity demonstrated that the H3.3 genes of the worm Urechis unicinctus [57], prolif- domain 486–499 is sufficient to activate the gene eration of hepatocytes and regeneration of hepatic [53]. Multiple pinpoint mutations in this domain tissue in mice [58], regulation of the metallothio- (486, 490, 491, 496, 497) attenuated the antisilenc- nine gene in man [59]. Presumably, the effects of ing effect by more than 80%. Mutations D486K, NF1 are underlain by complex DNA–protein and W496D and Y497D showed maximum efficiency protein–protein interactions realized at the chro- in attenuating the antisilencing effect of NF1-C. matin matrix level. These findings allow suggesting that 14 amino acid residues from the C-terminus of this factor medi- REFERENCES ate the activation of the silent transgene locus due to interaction with histone H3.3. 1. Iwafuchi-Doi, M. and Zaret, K.S., Pioneer tran- There were also conducted studies on HeLa scription factors in cell reprogramming, Genes & cells, in which it was demonstrated a silencing- Dev., 2014, vol. 28, pp. 2679–2692. 2. Wong, E.S., Thybert, D., and Schmitt, B.M., De- protector function of NF1, but only towards the coupling of evolutionary changes in transcription genes located distally, not proximally, to telo- factor binding and gene expression in mammals, meres. From this, it can be assumed that NF1 Genome Res., 2015, vol. 25, pp. 167–178. functions as a restrictor of the spreading of silent 3. Villar, D., Flicek, P., and Odom, D.T., Evolu- chromatin. It was hypothesized that NF1 does tion of transcription factor binding in metazoans– not behave as a classical transcriptional activator mechanisms and functional implications, Nature and performs rather as a mediator in establishing Reviews Genetics, 2014, vol. 15, pp. 221–233. a barrier for the spreading of silent chromatin by 4. de Mendoza, A., Sebé-Pedrós, A., Šestak, M.S., demarcating silent and active chromatin [54]. Matejcic, M., Torruella, G., Domazet-Loso, T., The assumed pattern of NF1 antisilencing ac- and Ruiz-Trillo, I., Transcription factor evolution in eukaryotes and the assembly of the regulatory tivity consists in the following. Telomeric gene toolkit in multicellular lineages, Proc. Natl. Acad. silencing is determined by the cooperation of Sci. USA, 2013, vol. 110, pp. 4858–4866. the complex consisting of SIR (Silent Informa- 5. Cheatle Jarvela, A.M. and Hinman, V.F., Evolu- tion Regulator) proteins (Sir-2, -3 and -4) with tion of transcription factor function as a mecha- telomere-binding proteins. As reported in yeasts nism for changing metazoan developmental [55], epigenetic silencing may spread along the gene regulatory networks, Evodevo, 2015, vol. 6, chromosome with transposition of the Sir protein pp. 3–11.

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