INTERFERON-INDUCIBLE GENES – TRANSCRIPTION REGULATORY REGIONS DATABASE (IIG-TRRD)

ANANKO E.A., BAZHAN S.I., BELOVA O.E.

Institute of Cytology and Genetics, (Siberian Branch of the Russian Academy of Sciences), 10 Lavrentieva ave., Novosibirsk, 630090 Russia

State Research Center of Virology and Biotechnology Vector, Koltsovo, Novosibirsk region, 133159 Russia

Keywords: interferon-inducible genes, transcription, regilatory regions, database, eukariotes, mechanism, transcription factor, gene networks, regulatory feedbacks

The volume of experimental data on regulation of functioning of both the interferon genes proper and IFN-inducible genes is growing fast. To generalize and systematize these data, we have designed an informational system for description of interferon-inducible gene transcription regulation IIG-TRRD (Interferon-Inducible Genes – Transcription Regulatory Regions Database). It is a constituent of the TRRD database [A.E. Kel’ et al., 1997] on transcription regulatory regions of eukaryotes and consists of two major parts: (1) a formalized description of the structure of gene regulatory regions and peculiarities of their regulation and (2) a hypertext-based description of interferon system functioning containing tables, figures, and schemes. The IIG-TRRD helps to visualize the functional interactions of genes and their products.

The current release of IIG-TRRD compiles the data on over 60 IFN-inducible genes and is available at http://www.bionet.nsc.ru/trrd/.

The information system for description of interferon-inducible gene transcription regulation IIG-TRRD (Interferon-Inducible Genes – Transcription Regulatory Regions Database) is a section of the TRRD database [A.E. Kel’ et al, 1997] on transcription regulatory regions, compiling the available information on regulation of gene systems controlling different functions of eukaryotic organisms [Podkolodnaya and Stepanenko, 1997; Anan’ko et al., 1997; O.V. Kel’ and A.E. Kel’, 1997; Merkulova et al., 1997; Ignat’eva et al., 1997]. IIG-TRRD consists of two major parts: (1) a formalized description of the structure of gene regulatory regions and peculiarities of their regulation in the TRRD format [A.E. Kel et al., 1995] and (2) a hypertext-based description of interferon system functioning containing tables, figures, and schemes, both cross-linked and linked to the formalized description. IIG-TRRD helps to follow the functional interactions of genes and their products. The interface of the IIG-TRRD front page listing its main sections is shown in Fig. 1. All section have a hierarchical structure and contain a number of cross-linked subsections.

Interferons are cytokines with a wide range of biological action. Interferons are involved in regulation of antiviral response, cell proliferation and differentiation, modulation of immune

and inflammatory responses through transcription regulation of IFN-inducible genes coding for various proteins. Investigation of the mechanisms of interferon expression regulation and their effects on the target genes is of great theoretical and applied importance, since it contributes to the understanding of the causes of organism function disorders. Analysis of the information from the IIG-TRRD database has demonstrated that the gene sets induced by type I and II interferons are partially overlapping (Table 1). IFN-inducible genes code for a variety of products: enzymes, nucleotide-binding proteins, transcription factors, major histocompatibility complex (MHC) class I and II antigens, regulatory proteins, lymphocyte antigens, certain cytokines and their receptors, Fc receptors with high affinity for IgG, and a number of proteins with yet unknown functions (Table 1). As a result, a complex gene network [Kolpakov et al.,

Table 1. Interferon-inducible genes contained in the IIG-TRRD database

Gene	Number of TRRD*	IFN inducibility		Function
	entries	a/b	g
REGULATORY PROTEINS
Transcription factor IRF-1	2	+	+	Transcription regulation of
Transcription factor ICSBP	1	–	+	interferons and interferon-inducible
Transcription factor IRF-2	1	+	–	genes
Transcription factor HNF-3b	1	.	+	Regulation of hepatocyte-specific gene expression
IP-10	1	+	+	Inflammatory response
Interleukin-6	1	–	+	Immunomodulatory effect
Interleukin-2	1	+	–	Immunomodulatory effect
Serine protease inhibitor Spi2.1	1			Antiproliferative effect
Cyclin-dependent kinase inhibitor CDKIp21	1		+	Antiproliferative effect
Inhibitor C1INH	1	+	+	Immunomodulatory effect
Genes 202, 204	2			Antiproliferative effect
Mx protein	1	+	–	Antiviral activity
Complement Bf protein	1	–	+	Immunomodulatory effect
ENZYMES
2′-5′ oligoadenylate synthetase OAS	2	+	–	Antiviral effect
Tryptophanyl-tRNA synthetase IFP-53	1	+/-	+	Tryptophan metabolism
Macrophage inducible nitric oxide synthase iNOS	1	–	+	Macrophage cytotoxicity
Indoleamine 2,3-dioxygenase IDO	1	+/-	+	Antiproliferative effect
Protein kinase PKR	1	+	+	Antiviral and antiproliferative effects, activation of NFk B
LYMPHOCYTE ANTIGENS
Lymphocyte antigens	2	+	+	Lymphocyte activation
RECEPTORS
IgG receptors Fcg RI	2	–	+	Antibody exposure
IL receptors	2	–	+	Increase in response to IL-2
CELL ADHESION PROTEINS
ICAM-1, VCAM-1	2	–	+	Antiinflammatory effect
NUCLEOTIDE-BINDING PROTEINS
Guanylate-binding proteins	3	+	+	Antiviral and antibacterial effects
RNA-binding protein	1	+	+/-	Antiviral effect
MAJOR HISTOCOMPATIBILITY COMPLEX COMPONENTS
MHC class II:	16	–	+	Antigen presentation, stimulation of T- and B-cell-mediated
MHC class I	8	+	+	immunity
OTHER GENES
p44, IFI-56K, ISG-15, ISG-54, and 6-16	5	+	–	Functions unknown
Acid cytokeratin K17, gene mig	2	–	+

1998] that regulates the functioning of interferon system is formed, that is, the system regulating interferon induction and action. A fragment of this gene network involving major relevant transcription factors (STAT1a , ISGF3, IRF-1, and IRF-2) is shown in Fig. 2.

Regulation of interferon system functioning illustrates the peculiarities of gene network organization:

1. Specificity of action, providing a directional response of the organism to different external stimuli (viral infection, etc.).

2. Functional crossing of gene activation pathways in various gene network nodes, providing the reliability of physiological response.

3. Occurrence of positive and negative regulatory feedbacks, that is, chains of events that lead to increase or decrease in gene expression. The different directionalities in regulatory feedbacks along with their nonsimultaneity allows the system to perform self-control and optimize the response depending on the strength of external stimuli through either increasing its efficiency or switching off the system.

4. Synergistic action of several factors providing nonadditive increase in response to simultaneous action of several inducers [Anan’ko et al., 1997].

Figure 1. The main components of the IFN gene network

The IIG-TRRD is linked with the GeneNet system for automated gene network visualization [Kolpakov et al., 1998], generating a more complete scheme of the gene network for IFN-dependent antiviral response.

Acknowledgments

The work was partially funded by the Russian Human Genome Program (12312 GCh-5), the State Committee of Science and Technology of the Russian Federation (“Database of regulatory genomic sequences”), Russian Foundation for Basic Research (96-04-50006), the US Department of Energy (No. OR00033-93CIS002), and Siberian Division of the Russian Academy of Sciences.

Figure 2. Interface of IIG-TRRD front page

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