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- Publisher Website: 10.1016/j.biocel.2014.04.013
- Scopus: eid_2-s2.0-84899844078
- PMID: 24794774
- WOS: WOS:000337774600019
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Article: HOXB5 binds to multi-species conserved sequence (MCS+9.7) of RET gene and regulates RET expression
Title | HOXB5 binds to multi-species conserved sequence (MCS+9.7) of RET gene and regulates RET expression |
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Authors | |
Keywords | Enhancer Transcription RET HOXB5 Hirschsprung disease |
Issue Date | 2014 |
Citation | International Journal of Biochemistry and Cell Biology, 2014, v. 51, n. 1, p. 142-149 How to Cite? |
Abstract | RET gene is crucial for the development of enteric nervous system, and dys-regulation of RET expression causes Hirschsprung disease. HOXB5 regulates RET transcription, and perturbations in transcriptional regulation by HOXB5 caused reduced RET expression and defective enteric nervous system development in mice. The mechanisms by which HOXB5 regulate RET transcription are unclear. Thus, unraveling the regulatory mechanisms of HOXB5 on RET transcription could lead to a better understanding of the etiology of Hirschsprung disease. In this study, we identified and confirmed HOXB5 binding to the multi-species conserved sequence (MCS+9.7) in the first intron of the RET gene. We developed a RET mini-gene reporter system, and showed that MCS+9.7 enhanced HOXB5 trans-activation from RET promoter in human neuroblastoma SK-N-SH cells and in chick embryos. The deletion of HOXB5 binding site interfered with HOXB5 trans-activation. Furthermore, transfection of HOXB5 induced endogenous RET transcription, enhanced the co-precipitation of TATA-box binding protein with the transcription start site of RET, and induced histone H3K4 trimethylation in chromatin regions upstream and downstream of RET transcription start site. In conclusion, (i) HOXB5 physically interacted with MCS+9.7 and enhanced RET transcription, (ii) HOXB5 altered chromatin conformation and histone modification of RET locus, which could facilitate the formation of transcription complex, and enhance RET transcription, (iii) expression of RET was mediated by a complex regulatory network of transcription factors functioning in a synergistic, additive and/or independent manners. Hence, dys-regulation of RET expression by HOXB5 could result in insufficient RET expression and Hirschsprung disease. © 2014 Elsevier Ltd. |
Persistent Identifier | http://hdl.handle.net/10722/220758 |
ISSN | 2023 Impact Factor: 3.4 2023 SCImago Journal Rankings: 1.079 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Zhu, Joe Jiang | - |
dc.contributor.author | Kam, Mandy Kaman | - |
dc.contributor.author | Garcia-Barceló, Maria Mercè | - |
dc.contributor.author | Tam, Paul Kwong Hang | - |
dc.contributor.author | Lui, Vincent Chi Hang | - |
dc.date.accessioned | 2015-10-16T06:50:28Z | - |
dc.date.available | 2015-10-16T06:50:28Z | - |
dc.date.issued | 2014 | - |
dc.identifier.citation | International Journal of Biochemistry and Cell Biology, 2014, v. 51, n. 1, p. 142-149 | - |
dc.identifier.issn | 1357-2725 | - |
dc.identifier.uri | http://hdl.handle.net/10722/220758 | - |
dc.description.abstract | RET gene is crucial for the development of enteric nervous system, and dys-regulation of RET expression causes Hirschsprung disease. HOXB5 regulates RET transcription, and perturbations in transcriptional regulation by HOXB5 caused reduced RET expression and defective enteric nervous system development in mice. The mechanisms by which HOXB5 regulate RET transcription are unclear. Thus, unraveling the regulatory mechanisms of HOXB5 on RET transcription could lead to a better understanding of the etiology of Hirschsprung disease. In this study, we identified and confirmed HOXB5 binding to the multi-species conserved sequence (MCS+9.7) in the first intron of the RET gene. We developed a RET mini-gene reporter system, and showed that MCS+9.7 enhanced HOXB5 trans-activation from RET promoter in human neuroblastoma SK-N-SH cells and in chick embryos. The deletion of HOXB5 binding site interfered with HOXB5 trans-activation. Furthermore, transfection of HOXB5 induced endogenous RET transcription, enhanced the co-precipitation of TATA-box binding protein with the transcription start site of RET, and induced histone H3K4 trimethylation in chromatin regions upstream and downstream of RET transcription start site. In conclusion, (i) HOXB5 physically interacted with MCS+9.7 and enhanced RET transcription, (ii) HOXB5 altered chromatin conformation and histone modification of RET locus, which could facilitate the formation of transcription complex, and enhance RET transcription, (iii) expression of RET was mediated by a complex regulatory network of transcription factors functioning in a synergistic, additive and/or independent manners. Hence, dys-regulation of RET expression by HOXB5 could result in insufficient RET expression and Hirschsprung disease. © 2014 Elsevier Ltd. | - |
dc.language | eng | - |
dc.relation.ispartof | International Journal of Biochemistry and Cell Biology | - |
dc.subject | Enhancer | - |
dc.subject | Transcription | - |
dc.subject | RET | - |
dc.subject | HOXB5 | - |
dc.subject | Hirschsprung disease | - |
dc.title | HOXB5 binds to multi-species conserved sequence (MCS+9.7) of RET gene and regulates RET expression | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1016/j.biocel.2014.04.013 | - |
dc.identifier.pmid | 24794774 | - |
dc.identifier.scopus | eid_2-s2.0-84899844078 | - |
dc.identifier.hkuros | 229577 | - |
dc.identifier.volume | 51 | - |
dc.identifier.issue | 1 | - |
dc.identifier.spage | 142 | - |
dc.identifier.epage | 149 | - |
dc.identifier.eissn | 1878-5875 | - |
dc.identifier.isi | WOS:000337774600019 | - |
dc.identifier.issnl | 1357-2725 | - |