CHD7 represses the retinoic acid synthesis enzyme ALDH1A3 during inner ear development

JCI Insight
Hui YaoDonna M Martin

Abstract

CHD7, an ATP-dependent chromatin remodeler, is disrupted in CHARGE syndrome, an autosomal dominant disorder characterized by variably penetrant abnormalities in craniofacial, cardiac, and nervous system tissues. The inner ear is uniquely sensitive to CHD7 levels and is the most commonly affected organ in individuals with CHARGE. Interestingly, upregulation or downregulation of retinoic acid (RA) signaling during embryogenesis also leads to developmental defects similar to those in CHARGE syndrome, suggesting that CHD7 and RA may have common target genes or signaling pathways. Here, we tested three separate potential mechanisms for CHD7 and RA interaction: (a) direct binding of CHD7 with RA receptors, (b) regulation of CHD7 levels by RA, and (c) CHD7 binding and regulation of RA-related genes. We show that CHD7 directly regulates expression of Aldh1a3, the gene encoding the RA synthetic enzyme ALDH1A3 and that loss of Aldh1a3 partially rescues Chd7 mutant mouse inner ear defects. Together, these studies indicate that ALDH1A3 acts with CHD7 in a common genetic pathway to regulate inner ear development, providing insights into how CHD7 and RA regulate gene expression and morphogenesis in the developing embryo.

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Citations

Oct 16, 2018·Wiley Interdisciplinary Reviews. Developmental Biology·Hiroshi Kurosaka
Jan 8, 2019·Genesis : the Journal of Genetics and Development·Berardino PetrelliAbraham Fainsod
Jun 4, 2019·Genesis : the Journal of Genetics and Development·Antionette L Williams, Brenda L Bohnsack
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May 8, 2021·Frontiers in Cell and Developmental Biology·Chiara ParodiValentina Massa
May 19, 2021·Developmental Biology·Vinodh BalendranDonna M Martin

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Datasets Mentioned

BETA
GSM1003473
GSE22341
SRP002695
while
GSE19409
SRP002214

Methods Mentioned

BETA
RNA-seq
coimmunoprecipitation
ChIP-seq
transfections
dissections
dissection
genotyping
PCR
transfection
hysterectomy

Software Mentioned

Bowtie2
DESeq
Excel
BLAST
Illustrator
Adobe
Galaxy
UCSC genome browser
MEME Suite
BEDTools

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