Multiomics analysis reveals that hepatocyte nuclear factor 1β regulates axon guidance genes in the developing mouse kidney.
Multiomics analysis reveals that hepatocyte nuclear factor 1β regulates axon guidance genes in the developing mouse kidney.
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多组学分析表明，肝细胞核因子1β调节发育中的小鼠肾脏中的轴突引导基因。
DOI：
10.1038/s41598-022-22327-5
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发表时间：
2022-10-20
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
转录因子肝细胞核因子1β（HNF-1β）是肾脏和其他上皮器官正常发育所必需的。在发育中的小鼠肾脏中，HNF-1β对于未成熟肾单位的分化和图案化以及输尿管芽（UB）的分支形态发生是必需的。在这里，我们使用ChIP测序（ChIP-seq）和RNA测序（RNA-seq）来鉴定胚胎小鼠肾脏中受HNF-1β调控的基因。ChIP-seq显示，HNF-1β与来自E14.5小鼠肾脏的染色质中的8284个位点结合。与先前的ATAC-seq和组蛋白修饰研究的比较显示，HNF-1β结合峰与开放染色质和转录激活的表观遗传标记（H3 K27乙酰化、H3 K4三甲基化、H3 K4单甲基化）共定位，表明结合位点是功能性的。为了研究HNF-1β结合和HNF-1β依赖性基因调控之间的关系，对从野生型和HNF-1β突变体胚胎肾纯化的UB细胞进行RNA-seq。共有1632个基因在HNF-1β缺陷的UB细胞中表现出表达降低，并且485个基因含有附近的HNF-1β结合位点，表明它们被HNF-1β直接激活。相反，HNF-1β直接抑制UB中526个基因的表达。与UB衍生细胞的snATAC-seq分析的比较表明，HNF-1β依赖性激活和抑制均与染色质可及性相关。通路分析显示，HNF-1β在发育中的肾脏中结合近68个轴突导向基因。RNA-seq分析显示Nrp 1、Sema 3c、Sema 3d、Sema 6a和Slit 2被HNF-1β激活，而Efna 1、Epha 3、Epha 4、Epha 7、Ntn 4、Plxna 2、Sema 3a、Sema 4 b、Slit 3、Srgap 1、Unc 5c和Unc 5d被HNF-1β抑制。RNAscope原位杂交显示Nrp 1、Sema 3c、Sema 3d、Sema 6a和Slit 2在野生型UB中表达，而在HNF-1β突变型UB中表达失调。这些研究表明，HNF-1β直接调节发育中小鼠肾脏中多个轴突导向基因的表达。轴突导向基因的失调可能是HNF-1β突变小鼠肾脏缺陷的基础。
The transcription factor hepatocyte nuclear factor 1β (HNF-1β) is essential for normal development of the kidney and other epithelial organs. In the developing mouse kidney, HNF-1β is required for the differentiation and patterning of immature nephrons and branching morphogenesis of the ureteric bud (UB). Here, we used ChIP-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) to identify genes that are regulated by HNF-1β in embryonic mouse kidneys. ChIP-seq revealed that HNF-1β binds to 8284 sites in chromatin from E14.5 mouse kidneys. Comparison with previous ATAC-seq and histone modification studies showed that HNF-1β binding peaks colocalized with open chromatin and epigenetic marks of transcriptional activation (H3K27 acetylation, H3K4 trimethylation, H3K4 monomethylation), indicating that the binding sites were functional. To investigate the relationship between HNF-1β binding and HNF-1β-dependent gene regulation, RNA-seq was performed on UB cells purified from wild-type and HNF-1β mutant embryonic kidneys. A total of 1632 genes showed reduced expression in HNF-1β-deficient UB cells, and 485 genes contained nearby HNF-1β binding sites indicating that they were directly activated by HNF-1β. Conversely, HNF-1β directly repressed the expression of 526 genes in the UB. Comparison with snATAC-seq analysis of UB-derived cells showed that both HNF-1β-dependent activation and repression correlated with chromatin accessibility. Pathway analysis revealed that HNF-1β binds near 68 axon guidance genes in the developing kidney. RNA-seq analysis showed that Nrp1, Sema3c, Sema3d, Sema6a, and Slit2 were activated by HNF-1β, whereas Efna1, Epha3, Epha4, Epha7, Ntn4, Plxna2, Sema3a, Sema4b, Slit3, Srgap1, Unc5c and Unc5d were repressed by HNF-1β. RNAscope in situ hybridization showed that Nrp1, Sema3c, Sema3d, Sema6a, and Slit2 were expressed in wild-type UB and were dysregulated in HNF-1β mutant UB. These studies show that HNF-1β directly regulates the expression of multiple axon guidance genes in the developing mouse kidney. Dysregulation of axon guidance genes may underlie kidney defects in HNF-1β mutant mice.
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影响因子：
11.8
作者：
Carroll, TJ;Park, JS;McMahon, AP
通讯作者：
McMahon, AP
影响因子：
3.7
作者：
Nie Y;Liu H;Sun X
通讯作者：
Sun X
DOI：
10.1016/j.jbc.2021.100965
发表时间：
2021-08
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Christie SM;Hao J;Tracy E;Buck M;Yu JS;Smith AW
通讯作者：
Smith AW
影响因子：
14.9
作者：
Bailey TL;Johnson J;Grant CE;Noble WS
通讯作者：
Noble WS
影响因子：
11.8
作者：
Costantini, Frank;Kopan, Raphael
通讯作者：
Kopan, Raphael