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Title: Positional Cloning of Zinc Finger Domain Transcription Factor Zfp69, a Candidate Gene for Obesity-Associated Diabetes Contributed by Mouse Locus Nidd/SJL}
Article:
Abstract:
Polygenic type 2 diabetes in mouse models is associated with obesity and results from a combination of adipogenic and diabetogenic alleles. Here we report the identification of a candidate gene for the diabetogenic effect of a QTL( Nidd/SJL, Nidd1) contributed by the SJL, NON, and NZB strains in outcross populations with New Zealand Obese( NZO) mice. A critical interval of distal chromosome 4( 2. 1 Mbp) conferring the diabetic phenotype was identified by interval-specific congenic introgression of SJL into diabetes-resistant C57BL/6J, and subsequent reporter cross with NZO. Analysis of the 10 genes in the critical interval by sequencing, qRT–PCR, and RACE–PCR revealed a striking allelic variance of Zfp69 encoding zinc finger domain transcription factor 69. In NZO and C57BL/6J, a retrotransposon( IAPLTR1a) in intron 3 disrupted the gene by formation of a truncated mRNA that lacked the coding sequence for the KRAB( Krüppel-associated box) and Znf-C2H2 domains of Zfp69, whereas the diabetogenic SJL, NON, and NZB alleles generated a normal mRNA. When combined with the B6. V-Lepob background, the diabetogenic Zfp69SJL allele produced hyperglycaemia, reduced gonadal fat, and increased plasma and liver triglycerides. mRNA levels of the human orthologue of Zfp69, ZNF642, were significantly increased in adipose tissue from patients with type 2 diabetes. We conclude that Zfp69 is the most likely candidate for the diabetogenic effect of Nidd/SJL, and that retrotransposon IAPLTR1a contributes substantially to the genetic heterogeneity of mouse strains. Expression of the transcription factor in adipose tissue may play a role in the pathogenesis of type 2 diabetes.
Introduction:
Type 2 diabetes results from the combination of insulin resistance and inadequate insulin secretion, the former being associated with obesity[1]. The risk of developing type 2 diabetes is to approximately 50% inherited[2]. Recently, numerous associations between single nucleotide polymorphisms and the diabetes risk in humans have been identified and confirmed[3]–[7]. However, little is known as to the functional consequences of these SNPs at the molecular, cellular, and physiological level. Obese mouse strains carrying the Lepob( ob) or the Lepdb( db) mutation have proven to be valuable models for the study of the pathophysiology and genetics of type 2 diabetes[8]. In these strains, the adipogenic mutation is necessary, but not sufficient for the development of severe hyperglycaemia and diabetes[9]. Thus, the diabetic phenotype appeared to be conferred by the background strain, and it was assumed that lean mice may carry diabetogenic and/or diabetes-protecting alleles. Furthermore, quantitative trait loci for obesity and hyperglycaemia were separated in outcross experiments of New Zealand Obese( NZO) mice and lean strains, proving the concept that diabetes is the result of a combination of adipogenic and diabetogenic alleles[10]–[13]. Subsequently, two genes that confer diabetes susceptibility of obese strains have been identified. Sorcs1 is a gene involved in microvasculature function, and contributes to diabetes in BTBR. V( B6)-Lepob mice[14]. A variant of Lisch-like was shown to be responsible in part for the diabetogenic effect of the DBA background in mice carrying the adipogenic db mutation[15]. Lisch-like has been suggested to be involved in the development of insulin-producing cells. Thus, positional cloning of mouse diabetes genes may provide major insights into the pathogenesis of obesity-associated diabetes. We have previously identified a QTL( Nidd/SJL) on distal chromosome 4 that aggravated and accelerated diabetes in an outcross population of NZO with the lean SJL strain[11],[12]. This QTL exhibited high LOD scores for the trait blood glucose, and reproducibly doubled the prevalence of diabetes in a NZOxSJL backcross population[12]. In addition, it markedly enhanced the effect of a second diabetes and obesity-modifying gene[16]. The chromosomal position of Nidd/SJL is similar to that of a previously described diabetogenic QTL( Nidd1, Figure 1) which has been identified in an outcross of NZO with NON[10]. Interestingly, the human syntenic region of Nidd1 and Nidd/SJL( human chromosome 1) comprises a QTL for reduced insulin secretion that was identified in the Pima Indian population[17]. Furthermore, in a recent metaanalysis of diabetogenic mouse QTL, distal chromosome 4 was among the 7 consensus regions with the highest combined LOD scores[18]. Thus, Nidd/SJL appeared to be a prime target for positional cloning of a novel mouse diabetes gene.
Discussion:
The present data identify the zinc finger domain transcription factor Zfp69 as the most likely candidate for the diabetogenic effect of the mouse QTL Nidd1 and Nidd/SJL which aggravates and accelerates obesity-associated diabetes in the NZO strain, and enhances hyperglycaemia in B6-ob/ob mice. The following arguments can be made in favour of this conclusion: Surprisingly, diabetes appears to be produced by ‘rescue’ of a loss-of-function variant of Zfp69: NZO mice and the diabetes-resistant B6 strain express a truncated mRNA, whereas the diabetogenic allele from SJL and NON produces a ‘normal’ expression of Zfp69. Identification of Zfp69 as the causal gene crucially depends on exclusion of other variations in the critical region. Firstly, Zfp69 was the only gene in the region exhibiting a significant differential expression in liver, adipose tissue, muscle or pancreas. Secondly, the T257I substitution in SMAP2 is outside of the functional domains of the ARF-GTPase activating protein[19],[20],[21], corresponds with the human sequence, and is classified as ‘tolerated’ by a method predicting deleterious substitutions[22]. Thirdly, the three non-synonymous exchanges in Col9a2 were also classified as ‘tolerated’. Furthermore, we failed to detect mRNA of Col9a2 in insulin-sensitive tissues or pancreas by PCR. The gene encodes a subunit of the extracellular matrix protein collagen type IX which is involved in cartilage and bone function[23]. Loss-of-function mutations cause multiple epiphyseal dysplasia in humans, and skeletal abnormalities in mice[28],[29]. Thus, none of the other nine genes in the critical region are likely candidates for the diabetogenic effect of Nidd/SJL. In order to further elucidate the diabetogenic effect of Nidd/SJL, and to link it with a cellular function of Zfp69SJL, we have studied B6. SJL-Nidd/SJL mice rendered obese by the ob mutation( B6. V-Lepob X B6. SJL-Nidd/SJL). Because of their monogenic obesity, these mice are much more homogeneous than the polygenic( NZOxSJL) F2 intercross population. The effects observed in these mice are consistent with the hypothesis that Nidd/SJL produced a redistribution of triglycerides from gonadal adipose tissue to ectopic stores such as liver, thereby causing hyperglycaemia through an aggravated insulin resistance. With such a scenario, we hypothesize that Zfp69SJL primarily causes a reduced storage capacity of epididymal adipose tissue. Zfp69SJL belongs to a family of transcription factors that comprise the conserved Krüppel-associated box( KRAB) in addition to the zinc finger DNA binding domain[25]. The KRAB domain appears to activate co-repressors, resulting in a suppression of target genes[30]. By analogy, we speculate that the normal Zfp69 allele suppresses genes required for expansion of adipose tissue stores. It should be noted, however, that this hypothesis requires definitive proof by a direct identification of the genes regulated by Zfp69. Interestingly, the above described scenario would explain the previously observed interaction between the diabetogenic Nidd/SJL allele and Nob1/Tbc1d1[12]. We have recently shown that the normal Tbc1d1 allele reduces fatty acid oxidation in muscle, thereby enhancing obesity and diabetes susceptibility[16]. Redistribution of triglycerides caused by Zfp69 would enhance the deleterious effects of the reduced fat oxidation, and explain the accelerated onset of diabetes observed in the presence of both diabetogenic alleles[12]. However, we cannot fully rule out additional effects of Zfp69 on other tissues such as muscle or pancreas. It should be noted that the diabetogenic effect of the Zfp69 variant is markedly dependent on interaction with other genes contributed by the background strain. Zfp69 requires obesity in order to produce hyperglycaemia( ‘diabesity’), and needs other diabetogenic alleles in order to produce beta cell failure, hypoinsulinaemia, and weight loss. So far, we could not detect beta cell destruction on the B6 background. On the NZO background, it was the interaction with NZO alleles on chromosomes 1 and 15 that enhanced the diabetogenic effect of Zfp69[Vogel et al., unpublished]. The production of an aberrant mRNA by alternative splicing is common in human inherited disease. Here, we have identified an unusual mechanism: a truncated Zfp69 mRNA was generated by insertion of a retrotransposon comprising a polyadenylation signal and a splicing acceptor site into intron 3. By a similar mechanism, expression of the endothelin B receptor is reduced in piebald mice[31]. Furthermore, it was shown recently that human soluble VEGF receptor is generated, and its abundance regulated, by intronic polyadenylation and alternative splicing[32]. In addition, an IAP retrotransposon causes intronic polyadenylation of the mouse Adamts13 gene[27]. Our in-silico search identified at least 7 additional genes with insertions of the IAPLTR1a that produced aberrant transcripts by the same mechanism of intronic polyadenylation and alternative splicing. Together with our functional data on the trapping of Zfp69 by IAPLTR1a, this finding supports the previous suggestion[26] that insertion of retroviral elements is an important contributor to the genetic heterogeneity of mouse strains.
Type 2 diabetes in humans as well as in obese mice is caused by a combination of adipogenic and diabetogenic gene variants . We have identified a gene that appears to be involved in the pathogenesis of hyperglycaemia in obese mice: in some mouse strains , the gene Zfp69 is disrupted by a retroviral transposon ( IAPLTR1a ) , which generates a truncated mRNA . Disruption of the gene was associated with a reduced susceptibility for diabetes , whereas the normal allele enhanced hyperglycaemia in obese mice . Zfp69 encodes a transcription factor which appears to interfere with lipid storage in adipose tissue , and thereby enhances lipid deposition in liver . In humans with type 2 diabetes , mRNA levels of the human orthologue of Zfp69 ( ZNF642 ) were increased in adipose tissue . Thus , the transcription factor ZFP69/ZNF642 may be involved in the pathogenesis of obesity-associated diabetes .