Article: HOXB5 cooperates with NKX2-1 in the transcription of human RET
| Title | HOXB5 cooperates with NKX2-1 in the transcription of human RET | ||||||
|---|---|---|---|---|---|---|---|
| Authors | Zhu, J1 GarciaBarcelo, MM1 Tam, PKH1 Lui, VCH1 | ||||||
| Issue Date | 2011 | ||||||
| Publisher | Public Library of Science. The Journal's web site is located at http://www.plosone.org/home.action | ||||||
| Citation | Plos One, 2011, v. 6 n. 6 [How to Cite?] DOI: http://dx.doi.org/10.1371/journal.pone.0020815 | ||||||
| Abstract | The enteric nervous system (ENS) regulates peristaltic movement of the gut, and abnormal ENS causes Hirschsprung's disease (HSCR) in newborns. HSCR is a congenital complex genetic disorder characterised by a lack of enteric ganglia along a variable length of the intestine. The receptor tyrosine kinase gene (RET) is the major HSCR gene and its expression is crucial for ENS development. We have previously reported that (i) HOXB5 transcription factor mediates RET expression, and (ii) mouse with defective HOXB5 activity develop HSCR phenotype. In this study, we (i) elucidate the underlying mechanisms that HOXB5 mediate RET expression, and (ii) examine the interactions between HOXB5 and other transcription factors implicated in RET expression. We show that human HOXB5 binds to the promoter region 5′ upstream of the binding site of NKX2-1 and regulates RET expression. HOXB5 and NKX2-1 form a protein complex and mediate RET expression in a synergistic manner. HSCR associated SNPs at the NKX2-1 binding site (-5G>A rs10900296; -1A>C rs10900297), which reduce NKX2-1 binding, abolish the synergistic trans-activation of RET by HOXB5 and NKX2-1. In contrast to the synergistic activation of RET with NKX2-1, HOXB5 cooperates in an additive manner with SOX10, PAX3 and PHOX2B in trans-activation of RET promoter. Taken together, our data suggests that HOXB5 in coordination with other transcription factors mediates RET expression. Therefore, defects in cis- or trans-regulation of RET by HOXB5 could lead to reduction of RET expression and contribute to the manifestation of the HSCR phenotype. © 2011 Zhu et al. | ||||||
| ISSN | 1932-6203 2011 Impact Factor: 4.092 2011 SCImago Journal Rankings: 0.519 | ||||||
| DOI | http://dx.doi.org/10.1371/journal.pone.0020815 | ||||||
| ISI Accession Number ID | WOS:000291355500045
Funding Information: This work was supported by research grants from the Hong Kong Research Grants Council (HKU7713/08M and HKU7654/07M to VCHL and MMGB respectively) and the University of Hong Kong Seed Funding Programme for Basic Research (200811159088) to VCHL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | ||||||
| PubMed Central ID | PMC3108997 | ||||||
| References | References in Scopus | ||||||
| Grants | Investigation of role of Hoxb5 in neural crest cell induction and maintenance in mouse embryos |
| dc.contributor.author | Zhu, J | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | GarciaBarcelo, MM | ||||||
| dc.contributor.author | Tam, PKH | ||||||
| dc.contributor.author | Lui, VCH | ||||||
| dc.date.accessioned | 2011-07-27T01:36:35Z | ||||||
| dc.date.available | 2011-07-27T01:36:35Z | ||||||
| dc.date.issued | 2011 | ||||||
| dc.description.abstract | The enteric nervous system (ENS) regulates peristaltic movement of the gut, and abnormal ENS causes Hirschsprung's disease (HSCR) in newborns. HSCR is a congenital complex genetic disorder characterised by a lack of enteric ganglia along a variable length of the intestine. The receptor tyrosine kinase gene (RET) is the major HSCR gene and its expression is crucial for ENS development. We have previously reported that (i) HOXB5 transcription factor mediates RET expression, and (ii) mouse with defective HOXB5 activity develop HSCR phenotype. In this study, we (i) elucidate the underlying mechanisms that HOXB5 mediate RET expression, and (ii) examine the interactions between HOXB5 and other transcription factors implicated in RET expression. We show that human HOXB5 binds to the promoter region 5′ upstream of the binding site of NKX2-1 and regulates RET expression. HOXB5 and NKX2-1 form a protein complex and mediate RET expression in a synergistic manner. HSCR associated SNPs at the NKX2-1 binding site (-5G>A rs10900296; -1A>C rs10900297), which reduce NKX2-1 binding, abolish the synergistic trans-activation of RET by HOXB5 and NKX2-1. In contrast to the synergistic activation of RET with NKX2-1, HOXB5 cooperates in an additive manner with SOX10, PAX3 and PHOX2B in trans-activation of RET promoter. Taken together, our data suggests that HOXB5 in coordination with other transcription factors mediates RET expression. Therefore, defects in cis- or trans-regulation of RET by HOXB5 could lead to reduction of RET expression and contribute to the manifestation of the HSCR phenotype. © 2011 Zhu et al. | ||||||
| dc.description.grant | Investigation of role of Hoxb5 in neural crest cell induction and maintenance in mouse embryos | ||||||
| dc.description.grantcode | 99817 | ||||||
| dc.description.nature | published_or_final_version | ||||||
| dc.identifier.citation | Plos One, 2011, v. 6 n. 6 [How to Cite?] DOI: http://dx.doi.org/10.1371/journal.pone.0020815 | ||||||
| dc.identifier.doi | http://dx.doi.org/10.1371/journal.pone.0020815 | ||||||
| dc.identifier.epage | e20815 | ||||||
| dc.identifier.hkuros | 187594 | ||||||
| dc.identifier.isi | WOS:000291355500045
Funding Information: This work was supported by research grants from the Hong Kong Research Grants Council (HKU7713/08M and HKU7654/07M to VCHL and MMGB respectively) and the University of Hong Kong Seed Funding Programme for Basic Research (200811159088) to VCHL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | ||||||
| dc.identifier.issn | 1932-6203 2011 Impact Factor: 4.092 2011 SCImago Journal Rankings: 0.519 | ||||||
| dc.identifier.issue | 6 | ||||||
| dc.identifier.pmcid | PMC3108997 | ||||||
| dc.identifier.pmid | 21677782 | ||||||
| dc.identifier.scopus | eid_2-s2.0-79958046096 | ||||||
| dc.identifier.spage | e20815 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/135531 | ||||||
| dc.identifier.volume | 6 | ||||||
| dc.language | eng | ||||||
| dc.publisher | Public Library of Science. The Journal's web site is located at http://www.plosone.org/home.action | ||||||
| dc.publisher.place | United States | ||||||
| dc.relation.ispartof | PLoS ONE | ||||||
| dc.relation.references | References in Scopus | ||||||
| dc.rights | Creative Commons: Attribution 3.0 Hong Kong License | ||||||
| dc.subject.mesh | Homeodomain Proteins - genetics - metabolism | ||||||
| dc.subject.mesh | Nuclear Proteins - genetics - metabolism | ||||||
| dc.subject.mesh | Proto-Oncogene Proteins c-ret - genetics - metabolism | ||||||
| dc.subject.mesh | Transcription Factors - genetics - metabolism | ||||||
| dc.subject.mesh | Transcription, Genetic | ||||||
| dc.title | HOXB5 cooperates with NKX2-1 in the transcription of human RET | ||||||
| dc.type | Article |
Author Affiliations
- The University of Hong Kong Li Ka Shing Faculty of Medicine