Positional cloning of zinc finger domain transcription factor Zfp69, a candidate gene for obesity-associated diabetes contributed by mouse locus Nidd/SJL.
Positional cloning of zinc finger domain transcription factor Zfp69, a candidate gene for obesity-associated diabetes contributed by mouse locus Nidd/SJL.
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DOI：
10.1371/journal.pgen.1000541
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发表时间：
2009-07
期刊：
影响因子：
4.5
通讯作者：
Joost HG
中科院分区：
文献类型：
--
作者：
Scherneck S;Nestler M;Vogel H;Blüher M;Block MD;Berriel Diaz M;Herzig S;Schulz N;Teichert M;Tischer S;Al-Hasani H;Kluge R;Schürmann A;Joost HG
小鼠模型中的多基因2型糖尿病与肥胖相关，并且是由脂肪形成和糖尿病形成等位基因的组合引起的。在这里，我们报告了在与新西兰肥胖（NZO）小鼠的异交群体中，SJL、NON和NZB品系贡献的QTL（Nidd/SJL、Nidd 1）致糖尿病效应的候选基因的鉴定。通过间隔特异性同源基因渗入SJL到糖尿病抗性C57 BL/6 J中，随后与NZO进行报告杂交，鉴定了赋予糖尿病表型的远端4号染色体的临界间隔（2.1 Mbp）。通过测序、qRT-PCR和RACE-PCR分析关键区间内的10个基因，发现编码锌指结构域转录因子69的Zfp 69的等位基因变异显著。在NZO和C57 BL/6 J中，内含子3中的反转录转座子（IAPLTR 1a）通过形成缺少Zfp 69的KRAB（Krüppel相关盒）和Znf-C2 H2结构域的编码序列的截短mRNA来破坏基因，而致糖尿病的SJL、NON和NZB等位基因产生正常的mRNA。当与B6.V-Lepob背景结合时，致糖尿病Zfp 69 SJL等位基因产生高血脂症，减少性腺脂肪，并增加血浆和肝脏甘油三酯。Zfp 69的人类直向同源物ZNF 642的mRNA水平在2型糖尿病患者的脂肪组织中显著增加。我们的结论是Zfp 69是Nidd/SJL致糖尿病效应的最可能候选者，并且反转录转座子IAPLTR 1a对小鼠品系的遗传异质性有很大贡献。脂肪组织中转录因子的表达可能在2型糖尿病的发病机制中起作用。人类和肥胖小鼠中的2型糖尿病是由脂肪形成和糖尿病形成基因变体的组合引起的。我们已经确定了一个似乎参与肥胖小鼠高脂血症发病机制的基因：在一些小鼠品系中，基因Zfp 69被逆转录病毒转座子（IAPLTR 1a）破坏，产生截短的mRNA。该基因的破坏与糖尿病易感性降低有关，而正常等位基因则会增强肥胖小鼠的高血糖症。Zfp 69编码一种转录因子，该因子似乎干扰脂肪组织中的脂质储存，从而增强肝脏中的脂质沉积。在患有2型糖尿病的人类中，Zfp 69（ZNF 642）的人类直系同源物的mRNA水平在脂肪组织中增加。因此，转录因子ZFP 69/ZNF 642可能参与肥胖相关糖尿病的发病机制。
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. 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.
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影响因子：
7
作者：
Ng, PC;Henikoff, S
通讯作者：
Henikoff, S
DOI：
10.1073/pnas.88.9.3608
发表时间：
1991-05-01
影响因子：
11.1
作者：
BELLEFROID, EJ;PONCELET, DA;MARTIAL, JA
通讯作者：
MARTIAL, JA
影响因子：
7.7
作者：
Plum, L;Kluge, R;Joost, HG
通讯作者：
Joost, HG
影响因子：
7.7
作者：
Reifsnyder, PC;Leiter, EH
通讯作者：
Leiter, EH
影响因子：
4.5
作者：
Dokmanovic-Chouinard M;Chung WK;Chevre JC;Watson E;Yonan J;Wiegand B;Bromberg Y;Wakae N;Wright CV;Overton J;Ghosh S;Sathe GM;Ammala CE;Brown KK;Ito R;LeDuc C;Solomon K;Fischer SG;Leibel RL
通讯作者：
Leibel RL