- Research article
- Open Access
Decreased expression levels of Ifi genes is associated to the increased resistance to spontaneous arthritis disease in mice deficiency of IL-1RA
- Xiaoyun Liu†1, 2,
- Yan Jiao†1, 2Email author,
- Yanhong Cao2, 4, 5,
- Nan Deng6,
- Yonghui Ma2,
- Karen A. Hasty2, 7,
- Andrew Kang6,
- Hong Chen3,
- John M. Stuart6, 7 and
- Weikuan Gu2, 7Email author
© The Author(s). 2016
Received: 31 March 2016
Accepted: 12 July 2016
Published: 2 August 2016
The mouse strain BALB/c deficient in IL-1 receptor antagonist protein (Il-1ra) develops spontaneous arthritis disease (SAD) while the strain DBA/1 IL1rn -/- with the same deficiency does not. Previously, we mapped a QTL on chromosome 1 for SAD and then developed a congenic mouse strain BALB.D1-1-/- that contains the QTL genomic fragment associated with resistance from DBA/1-/- on a BALB/c-/- background. The congenic strain was relatively resistant to spontaneous arthritis and had delayed onset and reduced severity of disease. We obtained whole genome expression profiles from the spleen of the congenic strain BALB.D1-1-/- and four other strains, the wild type BALB/c, DBA/1 and the deficient DBA/1 IL1rn -/- and the BALB/c IL1rn -/-. We then compared the similarities and differences between the congenic strain and the four parental strains. Here we report the selected potential causal genes based on differential expression levels as well as function of genes.
There is a considerable number of genes that are differentially expressed between the congenic strain and the three parental strains, BALB/c, DBA/1, and DBA/1-/-. However there only a few differentially expressed genes were identified by comparing the congenic strain and the BALB/c-/-strain. These differentially expressed genes are mainly from T-cell receptor beta chain (Tcrb) and interferon-activatable protein (Ifi) genes. These genes are also differentially expressed between congenic strain and BALB/c strains. However, their expression levels in the congenic strain are similar to that in DBA/1 and DBA/1-/-. The expression level of Tcrb-j gene is positively associated with two genes of Ifi gene 200 cluster.
Decreased expression levels of Ifi genes is associated to the increased resistance to spontaneous arthritis disease and with down regulation of expressions of Tcrb genes in the mouse congenic strain. Ifi genes may play an important role in the susceptibility to SAD in mice.
Identification of genes that regulate susceptibility to arthritis is essential in the selection of molecular targets for therapeutic application. The primary locus regulating collagen induced arthritis (CIA) was found to be within the major histocompatibility complex (MHC) loci [1–5]. This was expected because it was established that CIA in both rats and mice is MHC-linked [6–10]. Tremendous research has been done on the study of molecular mechanism of CIA model [11–15]. However, a considerable contribution to the arthritis is caused by a non-MHC-linked molecular mechanism [16–23]. Many non-MHC-linked loci have been identified [19, 22, 23], yet the causal genes for these QTL have not been known. Understanding of genes that regulate susceptibility to non-MHC-linked arthritis is essential for—the selection of molecular targets for therapy for non MHC-linked arthritis.
BALB/c and DBA/1 are important pairs of mouse strains. BALB/c and DBA/1 and C57B6/J mice share the same MHC (H-2d) haplotype; however, at the whole genome level they are genetically distant [17, 24]. In the mouse model, with a standard protocol, CIA is induced in DBA/1 and B6 [3, 10, 11, 25]. Under the same standard protocol, CIA could not be induced in BALB/c mice. The spontaneous arthritis (SAD) occurs in interleukin-1 (IL-1) receptor antagonist (IL-1rn) -deficient mice, which is dependent on non-MHC genetic bases [25, 26].
Over the last decade, we have been studying SAD in IL-1ra-deficient mice [25–29]. To better understand the pathogenesis of SAD, initially we used classical genetic techniques and bred susceptible and resistant mice to obtain an F2 generation and identified QTL associated with arthritis susceptibility . We obtained evidence for potential QTL on chromosomes 1, 6, 11, 12, and 14. The QTL on the chromosome 1 was the major regulator for the SAD. To confirm the importance of the QTL and to identify potential candidate genes within it, we conducted speed congenic breeding to transfer the QTL region from DBA/1 mice that are resistant to spontaneous arthritis into BALB/c-/- which are susceptible . Our congenic breeding was successful in identifying a QTL associated with the development of spontaneous arthritis. When a fragment of DNA from the DBA/1 strain was introduced onto a BALB/c background, arthritis was delayed in onset and was less severe. Using the congenic strains that we developed, the genomic region of the originally identified QTL was redefined into a region that is downstream from the peak region of our original mapping [26, 27, 29].
Microarrays have been used for the analysis of whole genome expression profiles for the more than a decade. They have developed as a mature technology not only in the producing of gene expression profiles but also in the analysis of differentially expressed genes. One of the useful applications of microarray-generated whole genome expression profiling is the identification of candidate genes that regulate a specific disease trait or a molecular pathway [28, 30–34].
According to the Ensembl database, the transferred region from DBA/1-/- to BALB/c-/- is between D1Mit110 and D1Mit209 on chromosome 1 with a size of 23.73 Mb which contains 320 genetic elements. Among those genes, 115 are identified as genes relevant to arthritis and its potential pathways . Although the number of genes seems large and to some degree difficult to specifically target candidate genes, comparison of the data from congenic strains provide a defined genomic region for their localization. The use of congenic strains enable us to analyze the effect of the transferred fragment within QTL region on global gene expression. Previously, we have been using the microarray tools for the study of differential gene expression comparing diseased knockout and normal wild type mice [28, 32, 33]. In this study, we compared gene expression profiles of the whole genome of the congenic strain and parental strains.
Mouse strains used in this study
IL-1 Receptor Antagonist
Normal strain originally from the Jackson laboratory
Normal strain originally from the Jackson laboratory
With mutation of IL1rn
With mutation of IL1rn
With mutation of IL1rn, with a piece of fragment from DBA/1, with BALB/c background.
The insertion and genotype of the congenic BALB.D1-1 mice was confirmed before RNA extraction and microarray analysis . Genomic DNA was extracted from tissues obtained by ear punch. The procedure used has been previously described . Briefly, DNA was extracted from the tissue and amplification of microsatellite markers conducted by polymerase chain reaction (PCR). PCR products were analyzed using poly-acrylamide gel electrophoresis using the Mega-Gel Dual High-Throughput Vertical Electrophoresis System (C.B.S. Scientific, Del Mar, CA).
RNA was extracted from spleens using a Trizol reagent (Invitrogen, CA). Total RNAs were purified using the RNeasy MinElute Cleanup Kit (Qiagen, CA). RNA quality and integrity were analyzed by the Agilent Bioanalyzer .
A starting amount of 200 ng of high-quality total RNA, with a RIN (RNA Integrity Score) number of more than seven, was used to generate cDNA and cRNA using the Illumina® TotalPrep™ RNA Amplification Kit (Ambion). For each of five individual samples, 1.5 ug of cRNA sample was hybridized overnight to Illumina mouse-6 v1.1 expression beadchips in a multiple step procedure according to the manufacturer’s instructions; the chips were washed, dried and scanned on the BeadArray Reader (Illumina, CA) and raw data were generated using BeadStudio 2.3.41 (Illumina, CA) [28, 33].
Analysis of microarray data
Raw data were normalized with quantile methodology using BeadStudio software. Four comparisons were made. The gene expression profiles of BALB.D1-1 compared to that of BALB/c-/-, BALB/c wild type, DBA/1-/-, and DBA/1 wild type. The Diff Score from the quantile method is a transformation of the p-value that provides directionality to the p-value based on the difference between the average signal in the reference group vs. the comparison group. For a p-value of 0.05, DiffScore = ± 13; For a p-value of 0.01, DiffScore = ± 22; For a p-value of 0.001, DiffScore = ± 33. The DiffScore in our initial analysis was set up as ± 10, to ensure we will not miss the potential candidate genes [33, 35].
Candidate and pathway analysis and construction
To identify candidate genes and construct pathway/connections, we correlated expression between candidate genes within QTL region and Il1rn, including Il1a, Il1b, Il1r1, Il1r2. For pathway analysis, we took full advantage of existing data of gene expression profiles at GeneNetwork at http://www.genenetwork.org/webqtl/main.py. We used gene expression data from spleens obtained from a set of recombinant inbred (RI) strains derived from C57BL/6 J (B6) and DBA/2 J (D2) [18, 36]. Data was generated using the Affymetrix GeneChip Mouse Gene 1.0 ST array (http://www.genenetwork.org/webqtl/main.py?FormID=sharinginfo&GN _AccessionId = 283). In the case of multiple probes, the one with highest expression level was chosen for the analysis . The gene networks were constructed using application tools in GeneNetwork. We constructed the gene network based on the Network Graph in combination with the Correlation Matrix. Network graph is often used to visualize multiple sets of interactions. The Spring Model layout (force reduction) was used for the graphic method for all graphic samples. We followed standard criteria for the strong, correlation, correlation, and none correlation. When the R value is equal or more than 0.7 or -0.7, we regard the correlation is strong positive or negative correlation. When the R value is between 0. 5 and 0.69 or -0. 5 and -0.69, the correlation exists but not as strong. Any R value between 0 and 0.5 or 0 and -0.5 is treated as none-to-weak-correlation [33, 35]. Initial analysis of relevance of genes to arthritis was conducted using PGMapper .
Similarities of whole genome gene expression profiles among different strains
Gene expression profiling between BALB.D1-1 and DBA/1 wild type
Because the BALB.D1-1 is under the BALB/c background with the spall piece of fragment from DBA background, one would expected to see the similarity of a small number of genes in the expression levels. However, the expression levels of more than 97% of genes between these two strains are similar. We then focused on the genes in the QTL region. We found that all of the genes in this region are expressed at the similar level between these two strains.” In particular, we noticed that all of the genes in the interferon activated (Ifi) gene family are similar between these two strains.
The 61 up regulated and 26 down regulated genes together with Il1a, Il1b, Il1r1, Il1r2, Il1rap, Il1rapl1, Il1rn are analyzed at Genenetwork. Using UTHSC Affy MoGene 1.0 ST Spleen (http://www.genenetwork.org/webqtl/main.py?FormID=sharinginfo&GN_AccessionId=283) were identified 162 probes. After eliminating some duplicate probes, 138 probes were used for the gene network construction . The gene Network shows that none of these genes directly connect to the Il1rn or other interleukin 1 family genes (Additional file 2: Figure S1).
Thus, none of the genes that showed differential expression are likely candidate genes that lead to the increased resistance to SAD.
Gene expression profiling between BALB.D1-1 and -/-DBA/1-/-
Both BALB.D1-1 and -/-DBA/1-/- are lack of IL1rn gene. Their gene expression levels showed more similarity in comparing to that between BALB.D1-1 and -/-DBA/1. We confirmed that the expression levels of Ifi gene family are similar between these two strains.
Gene expression profiling between BALB.D1-1 and BALB/c
Gene expression profiling between BALB.D1-1 and BALB/c-/-
Six of the 11 probes (Rnpep, Ifi203, Ifi204, Ifi205, Lefty1, Ifi202b) were found in the UTHSC Affy MoGene 1.0 ST Spleen database. Those 6 probes are analyzed together with Il1a, Il1b, Il1r1, Il1r2, Il1rap, Il1rapl1, Il1rn at Genenetwork. Using the whole genome expression profile from the spleen, we constructed the network of these genes (Fig. 5b), which shows that there is no strong correlation between the expression levels of IL1rn family and the interferon-activatable protein (Ifi) family members. We then constructed the gene network using whole genome expression profiles from the HZI T-Helper Cell Affymetrix M430v2 (http://www.genenetwork.org/webqtl/main.py?FormID=sharinginfo&GN_AccessionId=319) and HZI T-regulatory T cells (CD4 + CD25+) (http://www.genenetwork.org/webqtl/main.py?FormID=sharinginfo&GN_AccessionId=122). Data for gene networks of both T helper cells and T regulatory cells support that there is no strong connection between the expression levels of IL1rn family and the Ifi family members (Fig. 5c and d). Even after a further decrease of the threshold for significance to 0.35, there still no direct correlation between IL1rn and the Ifi family members.
Potential involvement of interferon-activatable protein and T-cell receptor beta chain genes in the resistance to SAD
We next compared the expression levels of all the 12 down regulated genes through the comparison between the congenic strain and the four parental strains above. As shown in Fig. 6, 11 of 12 down regulated probes in the congenic strain, compared to BALB-/-mice, were also down regulated when compared to that of BALB/c wt. None of the genes were down regulated when compared to that of -/-DBA/1-/-and DBA/1 wt. These data means that the expression levels of these genes are high in the BALB/c and BALB-/-while the expression levels of these genes are low in DBA/1 wt and -/-DBA/1-/-. Considering the fact that -/-DBA/1-/-is resistant to SAD while BALB-/-is susceptible to SAD, the decreased expression level of these genes in the congenic stain suggests that the increased resistance in congenic mice may be due to the down regulation of these genes.
Because T-cell receptor beta chain genes are not located on mouse chromosome 1. They are not the causal genes for the QTL. The only other group of differential expressed genes are the genes of Ifi cluster. If the genes of Ifi200 cluster is the causal genes for the QTL, then the decreased expression level of T-cell receptor beta chain genes should be caused by the decreased level of genes of Ifi200 cluster. Thus, there should be positive correlation at gene expression levels between at least one T-cell receptor beta chain gene and at least one gene in the Ifi200 cluster. We then identified probes for Ifi 200 cluster and one probe for T-cell receptor beta, joining region (Tcrb-j) from the whole genome profiles of mouse spleen in BXD strains. Our analysis shows that the expression levels of Ifi203 and Ifi205 are positively associated to that of Tcrv-j (Fig. 6b and c). Thus, in the case of congenic strain, the decreased expression levels of Ifi203 and Ifi205 may lead to the decreased expression levels of T-cell receptor beta chain genes. In turn, the down regulation of expression levels of T-cell receptor beta chain genes may lead to the increased resistance to spontaneous arthritis disease in the mouse congenic strain.
Real-time PCR for confirmation of expression level of Ifi203
Our multiple comparisons confirmed that the decreased expression levels of genes in T-cell receptor beta chain and Ifi cluster in the congenic strain are the major change that potentially leads to the increased resistance to SAD in the congenic strain in comparing to that of BALB/c-/-. The expression levels of these genes are similar to that in DBA and DBA/1-/-, which are resistant to the SAD. The expression of these genes is lower than that of BALB/c and BALB/c-/-, which are susceptible to SAD. There are considerable number of genes that are differentially expressed between the congenic strain and three other parental strains, the DBA, -/-DBA/1-/-and BALB/c because of the different genomic background and mutation of Il1r. However, there is only one difference between the congenic strain and BALB/c-/-. The difference is that in congenic mice, the genome region of QTL on chromosome 1 is replaced by the fragment from DBA while the entire remainder of the genome of BALB/c-/-are from the BALB/c strain. The small number of candidate genes derived from our analyses pave the way to final determine the causal gene in the congenic strain.
Our preliminary data indicated the Ifi gene 200 cluster contains the favorite candidate gene for the SAD resistance in the congenic strain. Among differentially expressed genes between congenic and BALB/c-/-, four genes in the Ifi gene 200 cluster are differentially expressed and are located in transferred genomic fragments in congenic strains. These genes are located in the transferred QTL genomic fragment on mouse chromosome 1, which is between D1Mit110 (167758517-167758653) and D1Mit209 (191493187-191493284). Our earlier analysis indicated that four candidate genes: Fcer1g, Fcgr3, Ifi202b, and Kmo are among the differentially expressed genes [29, 34]. Our current analysis indicates that the other three genes, Fcer1g, Fcgr3, and Kmo, were not differentially regulated in congenic strains compared to BALB/c-/- that is susceptible to spontaneous arthritis. Interferon-activatable protein has been reported as an immune suppressor [36, 38–40]. For example, Ifi202 is known as an interferon-inducible lupus susceptibility gene [36, 38]. Silencing of Ifi202b in tolerized CD8+ Ti cells abrogated the suppressive capacity of these cells. Recently the role of Ifi204 in the response to bacterial infection has been investigated . It is expected that in the near future much broad function of Ifi family genes in the infection and immune innate immune responses will be identified . Accordingly, it is very important to further investigate their candidacy.
The regulatory role of the T-cell receptor beta chain in the susceptibility of arthritis is well known [41–43]. Current information indicates that genes of T-cell receptor beta chain are not located in the transferred genomic fragment of the QTL region in the congenic strain. However, it is important to investigate if the genes between T-cell receptor beta chain family and Ifi family interact to down regulate SAD in the congenic strain.
In addition to the T-cell receptor beta chain and Ifi genes, we also detected the differential expression of Lefty1 in the QTL region. Early study indicated that Lefty1, Lefty2, and Nodal are expressed on the left side of developing mouse embryos and are implicated in L-R determination. Recently, because of the unique ability of Lefty to reroute the cell fate by making cells nonresponsive to diverse differentiation factors such as Nodal or other signals that require Egfcfc as a co-receptor, Lefty has become regarded as a determinant of cell stemness or differentiative events. There is no report for its role in arthritis, inflammation or infection. At present, we do not have enough information to explain its role in the congenic strains.
Our study was done with three replicates, each from female mice from each strain. The data may reflect a bias due to the use of female mice and may not represent that from male mice. Sex hormones have been shown to differentially regulate expression of Ifi202 . However, all the strains are measured at the same age stge. Therefore, the differences at least reflect the genomic variation in the female mice between congenic and other strains. We used the spleen as the organ for the RNA extraction and whole genome gene profiling . Although spleen as an organ important for immune, the phenotype of SAD in these mice were based on the joints. Therefore, we do not rule out that possibility that the data may not reflect what all happened in the joints. However, we believe that the molecular mechanism detected from this study is important to elucidate the causal gene for the congenic strain. Further study to directly link the candidate to the disease is necessary.
The “interferon-activatable protein” was labeled in the Illumina chip for a probe of LOC100040462. However, it lately has been validated as a transcription factor called Mndal, which is also a member of Ifi family gene. Interestingly, Zhang et al. in their paper indicated that Mndal is absent from DBA/2j . We assume that DBA/1, the strain we used in this study, is also absent. The increased level of expression level of Mndal in this case perhaps represents the Mndal gene from absent to present. However, the expression level from the DBA/1j genome detected by this probe is above the none-expression level (Absolute value over 118) while the expression level from the Balb/c genome is twice higher than that of the DBA/1j genome. As to its potential effect, it could be to interact with other genes in the Ifi family or to affect the expression level of heat hsp105/110hDa and Igkc2-112, which are only two known genes which showed the decreased expression between the congenic strain and the most closest parental strain, DBA-/-. However, because of the differential expression level of other genes in Ifi family, whether Mndal affect the expression of hsp105/110hDa and Igkc2-112 need further study.
Our data indicated that many differentially expressed among those mouse strains are not associated with Il1-rn. This result is not completely unexpected. First of all, SAD occurs in the mouse strain that is lack of expression of Il1-rn. One would predict that the gene expression profile of such a mouse strain does not reflect the pathways that involves the Il1-rn. Secondly, the causal genes derived from the comparison between the congenic strain BALB.D1-1 and BALB/c-/- are under the genomic background of lack of Il1-rn. Thus, the causal genes are in fact acting when there is a lack of Il1-rn. It is important to notice that with standard protocol, CIA has been induced in DBA/1 and B6 [3–5]. Under standard protocol, CIA could not be induced in BALB/c mice without modification. The SAD in interleukin-1 (IL-1) receptor antagonist (IL-1rn) -deficient mice is dependent on non-MHC (major histocompatibility complex) genes in mice. It is well-known that Il1-rn has played an important role in the arthritis. The role of Ifi family genes in SAD may act in the population that is non-MHC and lack of role of Il1-rn. On the other hand, the lack of association in the gene expression does not rule out the protein-protein interaction. The protein products of these two gene families may be directly interact or binding to each other.
Our study demonstrated the association of expression levels of the Ifi gene 200 cluster to the susceptibility of mice to SAD. Our data also suggest that the regulation of SAD by the Ifi gene 200 cluster is potentially through the regulation of genes of T-cell receptor beta chain.
CD4, cluster of differentiation 4; CIA, collagen-induced arthritis; Ifi, interferon-activatable protein; Il-1ra, IL-1 receptor antagonist protein; PCR, polymerase chain reaction; QTL, quantitative trait loci; SAD, spontaneous arthritis disease; Tcrb, T-cell receptor beta chain
This work was partially supported funding from The first hospital of Qiqihare City and merit grants (I01 BX000671 to WG, 1IPIBX001607 to JS) from the Department of Veterans Affairs and the Veterans Administration Medical Center in Memphis, TN, USA and National Natural Science Foundation of China (Project 81372996 to YJ; Project 81171679 to YHC), P.R. China.
Availability of supporting data
The data set(s) supporting the results of this article are included in the supplementary data of this manuscript.
YJ carried out the molecular genetic studies, participated in the microarray experiments, analyzed the data, and participating in drafting of the manuscript. XL carried out the animal breeding and genotyping, and revised the manuscript. YH carried out the animal breeding and revised the manuscript. ND carried out the animal breeding. YM participated in the microarray studies. HC participated in the design of the study, and helped to revise the manuscript. KH conceived of the study, and participated in its design and helped to draft the manuscript. AK conceived of the study, and participated in its design and helped to draft the manuscript. JS conceived of the study, and participated in its design and helped to draft the manuscript. WG conceived of the study, participated in its design, analyzed the data, and helped to finalize the manuscript. All authors read and approved the final manuscript.
The authors declare no competing interest.
Consent for publication
Ethics approval and consent to participate
This study did not involve human subjects or samples.
All mice have been maintained in the animal facility of the Department of Veterans Affairs Medical Center, Memphis. Experimental animal procedures and mouse husbandry were performed in accordance with the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals and approved by the VAMC Institutional Animal Care and Use Committee, Protocol #: 334310.
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