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

Yao, Hui; Hill, Sophie F.; Skidmore, Jennifer; Sperry, Ethan D.; Swiderski, Donald L.; Sanchez, Gilson J; Bartels, Cynthia F.; Raphael, Yehoash; Scacheri, Peter C.; Iwase, Shigeki; Martin, Donna M.

doi:10.1172/jci.insight.97440

Cited by 26 publications

(20 citation statements)

References 66 publications

(67 reference statements)

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“…5a). This result is consistent with previous studies showing that CHD7 both positively and negatively regulates expression of other genes 3,18,27 .…”

Section: Chd7 Regulates Genes Expression Chd7 Enrichment In the Genesupporting

confidence: 94%

CHD7 promotes neural progenitor differentiation in embryonic stem cells via altered chromatin accessibility and nascent gene expression

Yao

Hannum

Zhai

et al. 2020

Sci Rep

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CHARGE syndrome, a rare multiple congenital anomaly condition, is caused by haploinsufficiency of the chromatin remodeling protein gene CHD7 (Chromodomain helicase DNA binding protein 7). Brain abnormalities and intellectual disability are commonly observed in individuals with CHARGE, and neuronal differentiation is reduced in CHARGE patient-derived iPSCs and conditional knockout mouse brains. However, the mechanisms of CHD7 function in nervous system development are not well understood. In this study, we asked whether CHD7 promotes gene transcription in neural progenitor cells via changes in chromatin accessibility. We used Chd7 null embryonic stem cells (ESCs) derived from Chd7 mutant mouse blastocysts as a tool to investigate roles of CHD7 in neuronal and glial differentiation. Loss of Chd7 significantly reduced neuronal and glial differentiation. Sholl analysis showed that loss of Chd7 impaired neuronal complexity and neurite length in differentiated neurons. Genome-wide studies demonstrated that loss of Chd7 leads to modified chromatin accessibility (ATAC-seq) and differential nascent expression (Bru-Seq) of neural-specific genes. These results suggest that CHD7 acts preferentially to alter chromatin accessibility of key genes during the transition of NPCs to neurons to promote differentiation. Our results form a basis for understanding the cell stage-specific roles for CHD7-mediated chromatin remodeling during cell lineage acquisition.

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“…5a). This result is consistent with previous studies showing that CHD7 both positively and negatively regulates expression of other genes 3,18,27 .…”

Section: Chd7 Regulates Genes Expression Chd7 Enrichment In the Genesupporting

confidence: 94%

CHD7 promotes neural progenitor differentiation in embryonic stem cells via altered chromatin accessibility and nascent gene expression

Yao

Hannum

Zhai

et al. 2020

Sci Rep

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“…In addition to the pharmacologic manipulation of RA levels, genetic alterations in RA signaling are important causes of congenital craniofacial and ocular defects (Adams & Lammer, 1995;de la Cruz et al, 1984;Lammer et al, 1985;Maden, 2001;Rosa et al, 1986). Mutations in genes that are important for regulating RA synthesis (ALDH1A3, OMIM:600463; CHD7, OMIM:608892), degradation (CYP26B1, OMIM:605207), transport (STRA6; OMIM:610745), and signaling (RARβ; OMIM:180220) have all been identified in congenital diseases (Aldahmesh et al, 2013;Casey et al, 2011;Chassaing et al, 2013;Fares-Taie et al, 2013;Golzio et al, 2007;Laue et al, 2011;Micucci et al, 2014;Pagon, Graham Jr., Zonana, & Young, 1981;Pasutto et al, 2007;Roos et al, 2014;Srour et al, 2013;Yahyavi et al, 2013;Yao et al, 2018) Further, known downstream targets of RA within neural crest cells, including RAI1 (OMIM:607642),…”

Section: Congenital Craniofacial and Ocular Diseases Resulting Frommentioning

confidence: 99%

What's retinoic acid got to do with it? Retinoic acid regulation of the neural crest in craniofacial and ocular development

Williams

Bohnsack

2019

Genesis

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Vertebrate models, from zebrafish to mouse, and experimental tools, such as reporter transgenes, inhibitors of RA synthesis, and selective antagonists for RARs, have been successfully used to decipher retinoid functions during development at the cellular and molecular levels.Numerous examples from animal models and human diseases highlight the importance of RA in regulating neural crest contributions to craniofacial and ocular structures. The neural crest is a set of transient embryonic stem cells unique to vertebrates that originate at the border of the neural plate spanning the embryo from the diencephalon to the lumbosacral spinal cord. Neural crest cells undergo extensive and coordinated movements away from folds of the neural F I G U R E 1 Neural crest derivatives in the craniofacial region. (a) The neural crest is a transient population of embryonic stem cells that delaminate from the edge of the neural tube spanning from the diencephalon (Di) to the lumbosacral spinal cord (SpC). Neural crest cells that originate from the diencephalon and anterior mesencephalon (AM) migrate dorsal and ventral to the eye to populate the POM and frontonasal process (FNP). These cells migrate toward regions of high RA levels within the telencephalon (Te), POM, and frontonasal process. Neural crest cells from the posterior mesencephalon (PM) migrate into the first pharyngeal arch. Neural crest cells from the rhombencephalon, which are patterned by a RA gradient, migrate into the first through fourth pharyngeal arches in an anterior (AR) to posterior (PR) pattern. (b) The cranial neural crest is important in the development of the craniofacial skeleton. Neural crest cells in the frontonasal process give rise to the frontal bone (Fr), nasal bone (Na), and philtrum (Ph) in the midline of the face. The anterior portion of the first pharyngeal arch forms the maxillary (Mx) and zygomatic (Zy) bones while the posterior aspect gives rise to the mandible (Mn), The third and fourth pharyngeal arches both contribute to the hyoid (Ny) bone in the neck. (c) Neural crest cells, which are derived from the anterior mesenchyme and diencephalon, populate the periocular mesenchyme and migrate into the anterior segment of the eye. Ocular structures derived from the neural crest include the corneal stroma (CS), corneal endothelium (CEn), trabecular meshwork (TM), sclera (Scl), iris stroma (IS), uveal melanocytes (me), ciliary body muscle (CBM), and the tendons of the extraocular muscles (Tn). The corneal epithelium (CEp) and lens are derived from surface ectoderm while the ciliary body epithelium (CBE), retina (Ret), and retinal pigmented epithelium (RPE) arise from neuroepithelium. Schlemm's canal (SC) and extraocular muscles (EOM) originate from mesoderm. (d) Neural crest cells are also important in middle ear development. Vibrations are transmitted from the external ear, which consists of the pinna, auditory canal, and the tympanic membrane (Tym). The tympanic membrane is attached to the malleus in the middle ear. Both the malleus and the incus...

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“…Tbx1 is also responsive to Shh signaling in the pharyngeal endoderm (Yamagishi et al, 2003;Yamagishi et al, 2006), and in turn Shh expression is diminished in PAE embryos. CHARGE syndrome is a congenital condition caused by heterozygous loss-of-function of the chromodomain helicase DNA-binding protein (CHD7) gene (Vissers et al, 2004) that regulates downstream target gene expression via changes in nucleosome accessibility (Yao et al, 2018). Most of the CHARGE clinical features, including craniofacial malformations overlap with VAD syndrome (Maden, 2001), retinoic acid embryopathy (Lammer et al, 1985), and FASD phenotypes (Popova et al, 2016).…”

Section: Retinoic Acid Regulates Cncc Migrationmentioning

confidence: 99%

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

Petrelli

Bendelac

Hicks

et al. 2019

Genesis

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Summary Fetal Alcohol Spectrum Disorder (FASD) is a set of neurodevelopmental malformations caused by maternal consumption of alcohol during pregnancy. FASD sentinel facial features are unique to the disorder, and microcephaly is common in severe forms of FASD. Retinoic acid deficiency has been shown to cause craniofacial malformations and microcephaly in animal models reminiscent of those caused by prenatal alcohol exposure. Alcohol exposure affects the migration and survival of cranial neural crest cells, which are required for proper frontonasal prominence and pharyngeal arch development. Defects in craniofacial development are further amplified by the many downstream pathways that are transcriptionally controlled retinoic acid target genes, including Shh signaling. Recent evidence shows that alcohol exposure itself is sufficient to induce retinoic acid deficiency in the embryo. These data suggest that retinoic acid deficiency is an important underlying etiology of FASD. In disorders like Vitamin A Deficiency, FASD, DiGeorge (22q11.2 Deletion Syndrome), CHARGE, Smith‐Magenis, Matthew‐Wood, and Congenital Zika Syndromes, evidence is accumulating to link reduced retinoic acid signaling with developmental defects like craniofacial malformations and microcephaly. Research focus on characterizing the effects of retinoic acid deficiency during early development and on understanding the downstream signaling pathways involved in aberrant head, and craniofacial development will reveal underlying etiologies of these disorders.

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

Cited by 26 publications

References 66 publications

CHD7 promotes neural progenitor differentiation in embryonic stem cells via altered chromatin accessibility and nascent gene expression

CHD7 promotes neural progenitor differentiation in embryonic stem cells via altered chromatin accessibility and nascent gene expression

What's retinoic acid got to do with it? Retinoic acid regulation of the neural crest in craniofacial and ocular development

Insights into retinoic acid deficiency and the induction of craniofacial malformations and microcephaly in fetal alcohol spectrum disorder

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