Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing

Autor: Àlex Robert-Moreno, Krysta Voesenek, Silvia Naranjo, José Luis Gómez-Skarmeta, Hannie Kremer, John Economides, Elisa de la Calle-Mustienes, Berta Alsina, Haris Kokotas, Maria Grigoriadou, Nele Hilgert, Guy Van Camp, Michael B. Petersen, Felipe Moreno
Přispěvatelé: Junta de Andalucía, Ministerio de Educación y Ciencia (España), Oticon Foundation, Universidad Pablo de Olavide, Consejo Superior de Investigaciones Científicas (España)
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Male
Embryo
Nonmammalian
Genetics and epigenetic pathways of disease [NCMLS 6]
5' Flanking Region
Xenopus
DNA Mutational Analysis
Regulatory Sequences
Nucleic Acid
Hearing
Genetics(clinical)
Genetics (clinical)
In Situ Hybridization
Original Investigation
Genetics
Gene Expression Regulation
Developmental
Ear
Phenotype
Cell biology
Pedigree
medicine.anatomical_structure
Enhancer Elements
Genetic
Embryo
Female
Functional Neurogenomics [DCN 2]
Recombinant Fusion Proteins
POU3F4 protein
5' flanking region
Green Fluorescent Proteins
Biology
medicine
otorhinolaryngologic diseases
Animals
Humans
Inner ear
Enhancer
Hearing Loss
Gene
Transcription factor
Family Health
Base Sequence
Green fluorescent proteins
biology.organism_classification
Microscopy
Fluorescence
POU domain factors
Ear
Inner
Recombinant fusion proteins
POU Domain Factors
Human medicine
Otic vesicle
sense organs
Proteïnes
Gene Deletion
Oïda
Zdroj: Human Genetics
Human Genetics, 128, 411-9
Human Genetics, 128, 4, pp. 411-9
Digital.CSIC. Repositorio Institucional del CSIC
instname
Recercat. Dipósit de la Recerca de Catalunya
Human genetics
ISSN: 1432-1203
0340-6717
Popis: 9 páginas, 4 figuras.-- This article is distributed under the terms of the Creative Commons Attribution Noncommercial License.-- et al.
POU3F4 encodes a POU-domain transcription factor required for inner ear development. Defects in POU3F4 function are associated with X-linked deafness type 3 (DFN3). Multiple deletions affecting up to ~900-kb upstream of POU3F4 are found in DFN3 patients, suggesting the presence of essential POU3F4 enhancers in this region. Recently, an inner ear enhancer was reported that is absent in most DFN3 patients with upstream deletions. However, two indications suggest that additional enhancers in the POU3F4 upstream region are required for POU3F4 function during inner ear development. First, there is at least one DFN3 deletion that does not eliminate the reported enhancer. Second, the expression pattern driven by this enhancer does not fully recapitulate Pou3f4 expression in the inner ear. Here, we screened a 1-Mb region upstream of the POU3F4 gene for additional cis-regulatory elements and searched for novel DFN3 mutations in the identified POU3F4 enhancers. We found several novel enhancers for otic vesicle expression. Some of these also drive expression in kidney, pancreas and brain, tissues that are known to express Pou3f4. In addition, we report a new and smallest deletion identified so far in a DFN3 family which eliminates 3.9 kb, comprising almost exclusively the previous reported inner ear enhancer. We suggest that multiple enhancers control the expression of Pou3f4 in the inner ear and these may contribute to the phenotype observed in DFN3 patients. In addition, the novel deletion demonstrates that the previous reported enhancer, although not sufficient, is essential for POU3F4 function during inner ear development.
This work was supported by grants from the Spanish Ministry of Education and Science (BFU2007-60042/BMC, Petri PET2007_0158, CSD2007-00008) and Junta de Andalucía (Proyecto de Excelencia CVI-3488) to JLG-S, and the Oticon Foundation (Denmark) to MBP. CABD is institutionally supported by CSIC, Universidad Pablo de Olavide and Junta de Andalucía.
Databáze: OpenAIRE
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