Identification of HMX1 target genes: a predictive promoter model approach.

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serval:BIB_DE1779C5F19B
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Identification of HMX1 target genes: a predictive promoter model approach.
Journal
Molecular Vision
Author(s)
Boulling A., Wicht L., Schorderet D.F.
ISSN
1090-0535 (Electronic)
ISSN-L
1090-0535
Publication state
Published
Issued date
2013
Peer-reviewed
Oui
Volume
19
Pages
1779-1794
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: epublish
Abstract
PURPOSE: A homozygous mutation in the H6 family homeobox 1 (HMX1) gene is responsible for a new oculoauricular defect leading to eye and auricular developmental abnormalities as well as early retinal degeneration (MIM 612109). However, the HMX1 pathway remains poorly understood, and in the first approach to better understand the pathway's function, we sought to identify the target genes.
METHODS: We developed a predictive promoter model (PPM) approach using a comparative transcriptomic analysis in the retina at P15 of a mouse model lacking functional Hmx1 (dmbo mouse) and its respective wild-type. This PPM was based on the hypothesis that HMX1 binding site (HMX1-BS) clusters should be more represented in promoters of HMX1 target genes. The most differentially expressed genes in the microarray experiment that contained HMX1-BS clusters were used to generate the PPM, which was then statistically validated. Finally, we developed two genome-wide target prediction methods: one that focused on conserving PPM features in human and mouse and one that was based on the co-occurrence of HMX1-BS pairs fitting the PPM, in human or in mouse, independently.
RESULTS: The PPM construction revealed that sarcoglycan, gamma (35kDa dystrophin-associated glycoprotein) (Sgcg), teashirt zinc finger homeobox 2 (Tshz2), and solute carrier family 6 (neurotransmitter transporter, glycine) (Slc6a9) genes represented Hmx1 targets in the mouse retina at P15. Moreover, the genome-wide target prediction revealed that mouse genes belonging to the retinal axon guidance pathway were targeted by Hmx1. Expression of these three genes was experimentally validated using a quantitative reverse transcription PCR approach. The inhibitory activity of Hmx1 on Sgcg, as well as protein tyrosine phosphatase, receptor type, O (Ptpro) and Sema3f, two targets identified by the PPM, were validated with luciferase assay.
CONCLUSIONS: Gene expression analysis between wild-type and dmbo mice allowed us to develop a PPM that identified the first target genes of Hmx1.
Keywords
Animals, Base Sequence, Computational Biology/methods, Enzyme Assays, Gene Expression Profiling, Gene Expression Regulation, Genetic Testing, Genome/genetics, Glycine Plasma Membrane Transport Proteins/genetics, Glycine Plasma Membrane Transport Proteins/metabolism, Homeodomain Proteins/genetics, Homeodomain Proteins/metabolism, Humans, Luciferases/metabolism, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Models, Genetic, Molecular Sequence Data, Oligonucleotide Array Sequence Analysis, Promoter Regions, Genetic/genetics, Repressor Proteins/genetics, Repressor Proteins/metabolism, Reproducibility of Results, Sarcoglycans/genetics, Sarcoglycans/metabolism, Transcription Factors/genetics, Transcription Factors/metabolism
Pubmed
Web of science
Create date
26/09/2013 13:34
Last modification date
20/08/2019 16:02
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