Transcription factor Ap2b regulates the mouse autosomal recessive polycystic kidney disease genes, Pkhd1 and Cys1.
Transcription factor Ap2b regulates the mouse autosomal recessive polycystic kidney disease genes, Pkhd1 and Cys1.
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DOI：
10.3389/fmolb.2022.946344
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发表时间：
2022
影响因子：
5
通讯作者：
中科院分区：
文献类型：
--
作者：
转录因子Ap 2b（TFAP 2B）是AP-2家族的一种转录因子，与回文共有DNA序列5′-GCCN 3 -5GGC-3 ′结合。缺乏功能性Tfap 2b基因的小鼠在围产期或新生儿期死亡，伴有肾远端小管和集合管的囊性扩张，这是一种类似常染色体隐性遗传性多囊肾病（ARPKD）的表型。人类ARPKD是由哺乳动物中保守的PKHD 1、DZIP 1 L和CYS 1突变引起的。在这项研究中，我们研究了TFAP 2B作为Pkhd 1和Cys 1共同调节因子的潜在作用。我们利用5′RACE（5′ Rapid Amplification of cDNA Ends，5′RACE）技术确定了Cys 1的转录起始位点（Transcriptionstartsite，TSS）。生物信息学方法确定了顺式调控元件，包括两个TFAP 2B的共识结合位点，在上游调控区的Pkhd 1和Cys 1。基于在小鼠肾集合管细胞（mIMCD-3）中进行的报告基因测定，TFAP 2B激活Pkhd 1和Cys 1启动子，电迁移率变动测定（EMSA）证实TFAP 2B与计算机识别的位点结合。这些结果表明，Tfap 2b参与了肾上皮细胞基因调控网络，包括Pkhd 1和Cys 1。该网络的破坏损害肾小管分化，导致导管扩张，这是隐性PKD的标志。
Transcription factor Ap2b (TFAP2B), an AP-2 family transcription factor, binds to the palindromic consensus DNA sequence, 5′-GCCN3-5GGC-3’. Mice lacking functional Tfap2b gene die in the perinatal or neonatal period with cystic dilatation of the kidney distal tubules and collecting ducts, a phenotype resembling autosomal recessive polycystic kidney disease (ARPKD). Human ARPKD is caused by mutations in PKHD1, DZIP1L, and CYS1, which are conserved in mammals. In this study, we examined the potential role of TFAP2B as a common regulator of Pkhd1 and Cys1. We determined the transcription start site (TSS) of Cys1 using 5′ Rapid Amplification of cDNA Ends (5′RACE); the TSS of Pkhd1 has been previously established. Bioinformatic approaches identified cis-regulatory elements, including two TFAP2B consensus binding sites, in the upstream regulatory regions of both Pkhd1 and Cys1. Based on reporter gene assays performed in mouse renal collecting duct cells (mIMCD-3), TFAP2B activated the Pkhd1 and Cys1 promoters and electromobility shift assay (EMSA) confirmed TFAP2B binding to the in silico identified sites. These results suggest that Tfap2b participates in a renal epithelial cell gene regulatory network that includes Pkhd1 and Cys1. Disruption of this network impairs renal tubular differentiation, causing ductal dilatation that is the hallmark of recessive PKD.
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影响因子：
16.6
作者：
通讯作者：
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影响因子：
5
作者：
Moser, M;Dahmen, S;Buettner, R
通讯作者：
Buettner, R
影响因子：
11.8
作者：
Marneros, Alexander G.
通讯作者：
Marneros, Alexander G.
DOI：
10.1038/s41580-018-0028-8
发表时间：
2018-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Haberle V;Stark A
通讯作者：
Stark A
DOI：
10.1016/s1357-2725(01)00098-x
发表时间：
2002-01-01
影响因子：
4
作者：
Cheng, C;Ying, K;Mao, YM
通讯作者：
Mao, YM