CHD8short, a naturally-occurring truncated form of a chromatin remodeler lacking the helicase domain, is a potent transcriptional coregulator

Kunkel, Gary R.; Tracy, Jessica A.; Jalufka, Frank L; Lekven, Arne C.

doi:10.1016/j.gene.2017.10.058

Cited by 12 publications

(8 citation statements)

References 34 publications

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“…Therefore, we adopted an experimental protocol based on the dual luciferase system to examine zebrafish embryos. The luciferase reporter DNA plasmids were injected into zebrafish embryos at the one-cell developmental stage (Kunkel et al, 2018), together with expression constructs of interest, and luciferase activity was determined in the time window of promoter activity (24-48 hpi).…”

Section: Discussionmentioning

confidence: 99%

Identification of receptors for eight endocrine disrupting chemicals and their underlying mechanisms using zebrafish as a model organism

Huang

Lin

et al. 2020

Ecotoxicology and Environmental Safety

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Herein, eight common endocrine disrupting chemicals (EDCs) were exposed to zebrafish (Danio rerio) to investigate the relationship between different EDCs and their activated estrogen receptors. Under acute exposure, we identified five major malformation types whose incidence and deformity modes differed among EDCs. Luciferase analysis divided the EDC receptors into four categories: (i) triclosan (TCS), 17ß-estradiol (E2) and estriol (E3) mainly activated GPER expression; (ii) bisphenol A (BPA), p-(tert-octyl) phenol (POP), 17α-ethynylestradiol (EE2), E2 and E3 activated ERβ expression; (iii) E2 and E3 acted on both GPER and ERβ; and (iv) estrone (E1) and 9,9-bis(4-hydroxyphenyl)fluorene (BHPF) had little effect on the two receptors. In vivo immunofluorescence experiments on 96-hpf larvae provided evidence that TCS and POP acted on GPER and ERβ, respectively, while E2 acted on the two receptors simultaneously. Luciferase activities in the promoter regions of gper (À 986 to À 488) and erβ (À 1998 to À 1496) were higher than those in other regions, identifying these key regions as targets for transcription activity. TCS promoted GPER expression by acting on the JUND transcription factor, while POP promoted ERβ expression by activating the Foxl1 transcription factor. In contrast, E2 mainly regulated transcription of GPER and ERβ by Arid3a. These findings provide compelling evidence that different EDCs possess varying estrogen receptors, leading to differential regulatory pathways and abnormality symptoms. These results offer an experimental strategy and fundamental information to assess the molecular mechanisms of EDC-induced estrogen effects.

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Section: Discussionmentioning

confidence: 99%

Identification of receptors for eight endocrine disrupting chemicals and their underlying mechanisms using zebrafish as a model organism

Huang

Lin

et al. 2020

Ecotoxicology and Environmental Safety

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“…Mutations associated with ASD are mostly inactivating mutations that affect the helicase domain, which is known to play a role in chromatin remodelling. The short Duplin isoform still contains the nuclear localization signal and the βCAT‐binding site, making it an active inhibitor of the WNT signalling pathway [4]. The anti‐CHD8 antibody we used in this study does recognize both Duplin and the long isoforms.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we report 14-year-old monozygotic twins with myasthenia-like symptoms in whom we found a spontaneous heterozygous missense mutation in CHD8. This gene encodes the Chromosomal helicase domain protein 8 which, due to alternative splicing exists in two long 290 kDa (NM_001170629) and 262 kDa (NM_ 020920) [3], and several shorter isoforms; among them a C-terminally truncated isoform without the helicase domain, a protein called Duplin (for axis duplication inhibitor) [3,4]. CHD8 belongs to the CHD family of ATP-dependent chromatin remodelling enzymes that are responsible for regulation of DNA accessibility and thus for gene expression [5].…”

Section: Introductionmentioning

confidence: 99%

A spontaneous missense mutation in the chromodomain helicase DNA‐binding protein 8 (CHD8) gene: a novel association with congenital myasthenic syndrome

Lee

Petkova

Morales‐Gonzalez

et al. 2020

Neuropathology Appl Neurobio

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A spontaneous missense mutation in the chromodomain helicase DNA-binding protein 8 (CHD8) gene: a novel association with congenital myasthenic syndrome Aims: Congenital myasthenic syndromes (CMS) are characterized by muscle weakness, ptosis and episodic apnoea. Mutations affect integral protein components of the neuromuscular junction (NMJ). Here we searched for the genetic basis of CMS in female monozygotic twins. Methods: We employed whole-exome sequencing for mutation detection and Sanger sequencing for segregation analysis. Immunohistology was done with antibodies against CHD8, rapsyn, b-catenin (bCAT) and golgin on fibroblasts, human and mouse muscle. We recorded superresolution images of the NMJ using 3D-structured illumination microscopy. Results: We discovered a spontaneous missense mutation in CHD8 [chr14: g.21,884,051G>A, GRCh37.p11 | c.1732C>T, NM_0011 7062 | p.(R578C)], the gene encoding chromodomain helicase DNA-binding protein 8. This is the first missense mutation affecting Duplin, the short 110 kDa isoform of CHD8. It is known that CHD8/Duplin negatively regulates bCAT signalling in the WNT pathway and plays a role in chromatin remodelling. Inactivating CHD8 mutations are associated with autism spectrum disorder and intellectual disability in combination with facial dysmorphism, overgrowth and macrocephalus. No musclespecific phenotype has been reported to date. Co-immunostaining with rapsyn on human and mouse muscle revealed a strong presence of CHD8 at the NMJ being located towards the sarcoplasmic side of the rapsyn cluster, where it co-localizes with bCAT. Conclusion: We hypothesize CHD8 to have a role in the maintenance of the structural integrity and function of the NMJ. Both patients benefited from treatment with 3,4-diaminopyridine, a reversible blocker of voltage-gated potassium channels at the nerve terminal that prolongs the action potential and increases acetylcholine release.

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“…Total RNA was isolated from wild-type zebrafish embryos at designated developmental stages, converted to cDNA, and used in qRT-PCR experiments as described previously [29]. Gene-specific primers for znf143a were: 5′-GCGGTT CCAAAAGCAGATGAGC-3′ and 5′-CTTCCAGCTGA ACGGTCTGAGC-3′, and for znf143b were: 5′-CTCTAC TAAGATGGAGGCCACAG-3′ and 5′-CTGGATTCTA GGTGAACGACAGTC-3′ These primer sets were chosen for binding to nonhomologous regions of the two open reading frames (ORFs).…”

Section: Rna Isolation Cdna Synthesis Rt-pcrmentioning

confidence: 99%

Two paralogous znf143 genes in zebrafish encode transcriptional activator proteins with similar functions but expressed at different levels during early development

Huning

Kunkel

2020

BMC Mol and Cell Biol

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Background: ZNF143 is an important transcriptional regulator protein conserved in metazoans and estimated to bind over 2000 promoter regions of both messenger RNA and small nuclear RNA genes. The use of zebrafish is a useful model system to study vertebrate gene expression and development. Here we characterize znf143a, a novel paralog of znf143b, previously known simply as znf143 in zebrafish. This study reveals a comparison of quantitative and spatial expression patterns, transcriptional activity, and a knockdown analysis of both ZNF143 proteins. Results: ZNF143a and ZNF143b have a fairly strong conservation with 65% amino acid sequence identity, and both are potent activators in transient transfection experiments. In situ hybridization analyses of both znf143 mRNAs show that these genes are expressed strongly in regions of the brain at 24 h post fertilization in zebrafish development. A transient knockdown analysis of znf143 expression from either gene using CRISPR interference revealed similar morphological defects in brain development, and caused brain abnormalities in up to 50% of injected embryos. Although present in the same tissues, znf143a is expressed at a higher level in early development which might confer an evolutionary benefit for the maintenance of two paralogs in zebrafish. Conclusions: znf143a encodes a strong activator protein with high expression in neural tissues during early embryogenesis in zebrafish. Similar to its paralogous gene, znf143b, both znf143 genes are required for normal development in zebrafish.

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CHD8short, a naturally-occurring truncated form of a chromatin remodeler lacking the helicase domain, is a potent transcriptional coregulator

Cited by 12 publications

References 34 publications

Identification of receptors for eight endocrine disrupting chemicals and their underlying mechanisms using zebrafish as a model organism

Identification of receptors for eight endocrine disrupting chemicals and their underlying mechanisms using zebrafish as a model organism

A spontaneous missense mutation in the chromodomain helicase DNA‐binding protein 8 (CHD8) gene: a novel association with congenital myasthenic syndrome

Two paralogous znf143 genes in zebrafish encode transcriptional activator proteins with similar functions but expressed at different levels during early development

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