title: Identification of different mechanisms leading to PAX6 down-regulation as potential events contributing to the onset of Hirschsprung disease.
abstract: Hirschsprung disease (HSCR) is attributed to a failure of neural crest derived cells to migrate, proliferate, differentiate or survive in the bowel wall during embryonic Enteric Nervous System (ENS) development. This process requires a wide and complex variety of molecules and signaling pathways which are activated by transcription factors. In an effort to better understand the etiology of HSCR, we have designed a study to identify new transcription factors participating in different stages of the colonization process. A differential expression study has been performed on a set of transcription factors using Neurosphere-like bodies from both HSCR and control patients. Differential expression levels were found for CDYL, MEIS1, STAT3 and PAX6. A significantly lower expression level for PAX6 in HSCR patients, would suit with the finding of an over-representation of the larger tandem (AC)m(AG)n repeats within the PAX6 promoter in HSCR patients, with the subsequent loss of protein P300 binding. Alternatively, PAX6 is a target for DNMT3B-dependant methylation, a process already proposed as a mechanism with a role in HSCR. Such decrease in PAX6 expression may influence in the proper function of signaling pathways involved in ENS with the confluence of additional genetic factors to the manifestation of HSCR phenotype.
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain.
authors.forename: María Valle
authors.initials: MV
authors.lastname: Enguix-Riego
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Torroglosa
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain.
authors.forename: Raquel María
authors.initials: RM
authors.lastname: Fernández
authors.affiliation: Department of Pediatric Surgery, University Hospital Virgen del Rocío, Seville, 41013, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Moya-Jiménez
authors.affiliation: Department of Pediatric Surgery, General University Hospital Gregorio Marañon, Madrid, 28009, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: de Agustín
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Antiñolo
authors.affiliation: Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain.|Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain.
authors.forename: Salud
authors.initials: S
authors.lastname: Borrego
mesh_terms: D000483:Alleles; D016022:Case-Control Studies; D002675:Child, Preschool; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D015536:Down-Regulation; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D017615:Enteric Nervous System; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D018895:Microsatellite Repeats; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D000071841:PAX6 Transcription Factor / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D050881:E1A-Associated p300 Protein; D000071841:PAX6 Transcription Factor; D014157:Transcription Factors; D000097584:DNA Methyltransferase 3B