Comparative Genomics-Based Identification and Analysis of Cis-Regulatory Elements

Ogino, Hitoshi; Ochi, Hiroki; Uchiyama, Chihiro; Louie, Sarah H.; Grainger, Robert M.

doi:10.1007/978-1-61779-992-1_15

Cited by 10 publications

(10 citation statements)

References 31 publications

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“…The genomic Nkx3.1 locus contains a candidate enhancer region for the mouse prostate, which is located at −7 kb from the 3′-coding region of Nkx3.1 ( 46 ). Using the rVISTA genome browser and MultiPipmaker ( 47 ), we found that the 3′-region of Nkx3.1 was conserved among mammals but not in other vertebrates (data not shown). The conserved region was illustrated by a comparison of the human, mouse, and opossum loci ( Figure 5 H), which contained several Smad-binding elements.…”

Section: Resultsmentioning

confidence: 99%

Essential Roles of Epithelial Bone Morphogenetic Protein Signaling During Prostatic Development

et al. 2014

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Prostate is a male sex-accessory organ. The prostatic epithelia consist primarily of basal and luminal cells that differentiate from embryonic urogenital sinus epithelia. Prostate tumors are believed to originate in the basal and luminal cells. However, factors that promote normal epithelial differentiation have not been well elucidated, particularly for bone morphogenetic protein (Bmp) signaling. This study shows that Bmp signaling prominently increases during prostatic differentiation in the luminal epithelia, which is monitored by the expression of phosphorylated Smad1/5/8. To elucidate the mechanism of epithelial differentiation and the function of Bmp signaling during prostatic development, conditional male mutant mouse analysis for the epithelial-specific Bmp receptor 1a (Bmpr1a) was performed. We demonstrate that Bmp signaling is indispensable for luminal cell maturation, which regulates basal cell proliferation. Expression of the prostatic epithelial regulatory gene Nkx3.1 was significantly reduced in the Bmpr1a mutants. These results indicate that Bmp signaling is a key factor for prostatic epithelial differentiation, possibly by controlling the prostatic regulatory gene Nkx3.1.

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Section: Resultsmentioning

confidence: 99%

Essential Roles of Epithelial Bone Morphogenetic Protein Signaling During Prostatic Development

et al. 2014

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“…These results prompted us to investigate whether Mafb is a direct target gene of AR signaling during urethral masculinization. To identify androgen response regions in the Mafb locus, we compared its sequences in mice and other species using the ECR browser (34). Mafb is composed of 1 exon, and its CDS is significantly conserved among many vertebrate species.…”

Section: Ar Signaling Regulates Mafb Expression Through the Mafb 3utrmentioning

confidence: 99%

Androgen Regulates Mafb Expression Through its 3′UTR During Mouse Urethral Masculinization

et al. 2015

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External genitalia are prominent organs showing hormone-dependent sexual differentiation. Androgen is an essential regulator of masculinization of the genital tubercle, which is the anlage of external genitalia. We have previously shown that v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MAFB) is an androgen-inducible regulator of embryonic urethral masculinization in mice. However, it remains unclear how androgen regulates Mafb expression. The current study suggests that the Mafb 3' untranslated region (UTR) is an essential region for its regulation by androgen. We identified 2 functional androgen response elements (AREs) in Mafb 3'UTR. Androgen receptor is bound to such AREs in 3'UTR during urethral masculinization. In addition to 3'UTR, Mafb 5'UTR also showed androgen responsiveness. Moreover, we also demonstrated that β-catenin, one of genital tubercle masculinization factors, may be an additional regulator of Mafb expression during urethral masculinization. This study provides insights to elucidate mechanisms of gene regulation through AREs present in Mafb 3'UTR for a better understanding of the processes of urethral masculinization.

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“…In order to identify regulatory sequences that activate Hnf1b gene expression in the developing kidney, we searched for evolutionary conserved non-coding sequences (CNSs) as candidates for enhancers. Using in silico methods that allow detailed inspection of sequence conservation profiles across several genomes 29 , we compared the genomic sequence of a 157 kb segment encompassing the mouse ( Mus musculus ) Hnf1b gene with the orthologous intervals in human ( Homo sapiens ), rat ( Rattus norvegicus ), opossum ( Monodelphis domestica ), chicken ( Gallus gallus ), frog ( Xenopus tropicalis ) and zebrafish ( Danio rerio ). This analysis identified one CNS (called CNS1) conserved in all species, except zebrafish, located 33.4 kb upstream the Hnf1b transcription start site in mouse and a second one (CNS2) located in the 4 th intron of Hnf1b conserved in all species examined (Fig.…”

Section: Resultsmentioning

confidence: 99%

Hnf1b renal expression directed by a distal enhancer responsive to Pax8

Goea

Buisson

Bello

et al. 2022

Preprint

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Xenopus provides a simple and efficient model system to study nephrogenesis and explore the mechanisms causing renal developmental defects in human. Hnf1b (hepatocyte nuclear factor 1 homeobox b), a gene whose mutations are the most commonly identified genetic cause of developmental kidney disease, is required for the acquisition of a proximo-intermediate nephron segment in Xenopus as well as in mouse. Genetic networks involved in Hnf1b expression during kidney development remain poorly understood. We decided to explore the transcriptional regulation of Hnf1b in the developing Xenopus pronephros and mammalian renal cells. Using phylogenetic footprinting, we identified an evolutionary conserved sequence (CNS1) located several kilobases (kb) upstream the Hnf1b transcription start and harboring epigenomic marks characteristics of a distal enhancer in embryonic and adult renal cells in mammals. By means of functional expression assays in Xenopus and mammalian renal cell lines we showed that CNS1 displays enhancer activity in renal tissue. Using CRISPR/cas9 editing in Xenopus tropicalis, we demonstrated the in vivo functional relevance of CNS1 in driving hnf1b expression in the pronephros. We further showed the importance of Pax8-CNS1 interaction for CNS1 enhancer activity allowing us to conclude that Hnf1b is a direct target of Pax8. Our work identified for the first time a Hnf1b renal specific enhancer and may open important perspectives into the diagnosis for congenital kidney anomalies in human, as well as modeling HNF1B-related diseases.

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Comparative Genomics-Based Identification and Analysis of Cis-Regulatory Elements

Cited by 10 publications

References 31 publications

Essential Roles of Epithelial Bone Morphogenetic Protein Signaling During Prostatic Development

Essential Roles of Epithelial Bone Morphogenetic Protein Signaling During Prostatic Development

Androgen Regulates Mafb Expression Through its 3′UTR During Mouse Urethral Masculinization

Hnf1b renal expression directed by a distal enhancer responsive to Pax8

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