| First Author | Shao A | Year | 2022 |
| Journal | Sci Rep | Volume | 12 |
| Issue | 1 | Pages | 17586 |
| PubMed ID | 36266461 | Mgi Jnum | J:330633 |
| Mgi Id | MGI:7379811 | Doi | 10.1038/s41598-022-22327-5 |
| Citation | Shao A, et al. (2022) Multiomics analysis reveals that hepatocyte nuclear factor 1beta regulates axon guidance genes in the developing mouse kidney. Sci Rep 12(1):17586 |
| abstractText | The transcription factor hepatocyte nuclear factor 1beta (HNF-1beta) is essential for normal development of the kidney and other epithelial organs. In the developing mouse kidney, HNF-1beta 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-1beta in embryonic mouse kidneys. ChIP-seq revealed that HNF-1beta binds to 8284 sites in chromatin from E14.5 mouse kidneys. Comparison with previous ATAC-seq and histone modification studies showed that HNF-1beta 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-1beta binding and HNF-1beta-dependent gene regulation, RNA-seq was performed on UB cells purified from wild-type and HNF-1beta mutant embryonic kidneys. A total of 1632 genes showed reduced expression in HNF-1beta-deficient UB cells, and 485 genes contained nearby HNF-1beta binding sites indicating that they were directly activated by HNF-1beta. Conversely, HNF-1beta directly repressed the expression of 526 genes in the UB. Comparison with snATAC-seq analysis of UB-derived cells showed that both HNF-1beta-dependent activation and repression correlated with chromatin accessibility. Pathway analysis revealed that HNF-1beta 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-1beta, whereas Efna1, Epha3, Epha4, Epha7, Ntn4, Plxna2, Sema3a, Sema4b, Slit3, Srgap1, Unc5c and Unc5d were repressed by HNF-1beta. RNAscope in situ hybridization showed that Nrp1, Sema3c, Sema3d, Sema6a, and Slit2 were expressed in wild-type UB and were dysregulated in HNF-1beta mutant UB. These studies show that HNF-1beta 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-1beta mutant mice. |
