Autism‐linked <scp>CHD</scp> gene expression patterns during development predict multi‐organ disease phenotypes

Kasah, Sahrunizam; Oddy, Christopher; Basson, M. Albert

doi:10.1111/joa.12889

Cited by 15 publications

(15 citation statements)

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“…In addition, 50% of Chd8 neo/− embryos showed unilateral anopthalmia (Additional file 1 : Fig. S2H), in agreement with strong Chd8 expression in the developing eye [ 35 ]. Taken together, these data suggested that brain growth responds to reductions in CHD8 levels in a non-linear manner, with heterozygotes and mild hypomorphs exhibiting brain overgrowth, and severe hypomorphs presenting with brain hypoplasia.…”

Section: Resultsmentioning

confidence: 60%

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Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development

et al. 2021

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Background CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. Methods To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. Results Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. Conclusions Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work.

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Section: Resultsmentioning

confidence: 60%

“…Chd8 neo/neo mice exhibited a significant reduction in postnatal survival (Table 1 ). As CHD8 is expressed in multiple tissues during development [ 35 ], this postnatal lethality is likely a consequence of congenital defects affecting essential organs.…”

Section: Resultsmentioning

confidence: 99%

Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development

et al. 2021

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“…Both neuronal and glial cells are implicated in ASD pathobiology (Ballas et al, 2009;Derecki et al, 2012;Gupta et al, 2014;Kasah et al, 2018;Morgan et al, 2012;Morgan et al, 2010;Suzuki et al, 2013;Voineagu et al, 2011). The XP-broad network is expressed across cell types, while the XP-specific network is enriched in neuronal cells.…”

Section: Non-neuronal Cells Harbor Dysregulated Transcription In Broamentioning

confidence: 99%

“…Although valuable, such models ignore potential impacts of ASD genetics in other cellular or developmental contexts. For example, rASD genes are linked to biological processes related to non-neuronal cell types including microglia, astrocytes, and leukocytes (Ballas et al, 2009;Derecki et al, 2012;Gupta et al, 2014;Kasah et al, 2018;Pramparo et al, 2015;Suzuki et al, 2013;Voineagu et al, 2011). Likewise, genetic variants related to brain processes, diseases, and disorders can modulate gene expression in cell types other than neurons and tissues other than brain (Lin et al, 2018;Lombardo et al, 2018;Pardinas et al, 2018;Wright et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Autism genetics perturb prenatal neurodevelopment through a hierarchy of broadly-expressed and brain-specific genes

Gazestani¹,

Chiang²,

Courchesne³

et al. 2020

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Numerous genes are associated with autism spectrum disorder (ASD); however, it remains unclear how most ASD risk genes influence neurodevelopment and result in similar traits. Recent genetic models of complex traits suggest non-tissue-specific genes converge on core disease genes; so we analyzed ASD genetics in this context. We found ASD risk genes partition cleanly into broadly-expressed and brain-specific genes. The two groups show sequential roles during neurodevelopment with broadly-expressed genes modulating chromatin remodeling, proliferation, and cell fate, while brain-specific risk genes are involved in neural maturation and synapse functioning. Broadly-expressed risk genes converge onto brain-specific risk genes and core neurodevelopmental genes through regulatory networks including PI3K/AKT, RAS/ERK, and WNT/ -catenin signaling pathways. Broadly-expressed and brain-specific risk genes show unique properties, wherein the broadly-expressed risk gene network is expressed prenatally and conserved in non-neuronal cells like microglia. However, the brain-specific gene network expression is limited to excitatory and inhibitory neurons, spanning prenatal to adulthood. Furthermore, the two groups are linked differently to comorbidities associated with ASD. Collectively, we describe here the organization of the genetic architecture of ASD as a hierarchy of broadlyexpressed and brain-specific genes that disrupt successive stages of core neurodevelopmental processes.Recent studies present an alternate model of complex traits where the functional impact of genetic aberrations propagates through gene regulatory networks to converge on downstream core processes related to the trait (Boyle et al., 2017;Califano and Alvarez, 2017;Courchesne et al., 2020;Gazestani et al., 2019;Iakoucheva et al., 2019;Liu et al., 2019). In contrast to the single-group rASD network model, if the polygenic and omnigenic models are relevant to ASD, they would suggest that many risk genes are not necessarily part of underlying neural mechanisms in ASD. Rather many rASD genes would be broadly-expressed across many tissues, but regulate core neurodevelopmental processes underlying ASD (Boyle et al., 2017;Califano and Alvarez, 2017;Courchesne et al., 2020;Gazestani et al., 2019). Moreover, by emphasizing the gene regulatory networks, these alternative models suggest that, to the extent that the gene regulatory networks are preserved, the dysregulation could also be reflected in non-neuronal cells . Supporting these ideas, many rASD genes are broadly-expressed across tissues and strongly enriched for gene expression regulators such as chromatin remodelers, transcription factors, and modulators of signaling pathways (Courchesne et al., 2020;Courchesne et al., 2019;Werling et al., 2020). Similarly, genome wide association studies (GWAS) and whole genome sequencing both highlight the important role of broadly functional eQTLs and gene regulatory networks in ASD liability (Brandler et al., 2018;Courchesne et al., 2020;Grove et al., 2019).The fundamen...

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“…Chromodomain helicase DNA-binding protein 8 (CHD8) is a member of ATP-dependent chromatin remodeling protein in the CHD family [19]. CHD8 is related to the development of autism [20,21], and involved in embryonic development and apoptosis of vascular smooth muscle cells [19,22]. However, the function of CHD8 in myocardial I/R injury and H/R is not known yet.…”

Section: Introductionmentioning

confidence: 99%

Critical roles of microRNA-141-3p and CHD8 in hypoxia/reoxygenation-induced cardiomyocyte apoptosis

et al. 2020

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Background: Cardiovascular diseases are currently the leading cause of death in humans. The high mortality of cardiac diseases is associated with myocardial ischemia and reperfusion (I/R). Recent studies have reported that micro-RNAs (miRNAs) play important roles in cell apoptosis. However, it is not known yet whether miR-141-3p contributes to the regulation of cardiomyocyte apoptosis. It has been well established that in vitro hypoxia/reoxygenation (H/R) model can follow in vivo myocardial I/R injury. This study aimed to investigate the effects of miR-141-3p and CHD8 on cardiomyocyte apoptosis following H/R. Results:We found that H/R remarkably reduces the expression of miR-141-3p but enhances CHD8 expression both in mRNA and protein in H9c2 cardiomyocytes. We also found either overexpression of miR-141-3p by transfection of miR-141-3p mimics or inhibition of CHD8 by transfection of small interfering RNA (siRNA) significantly decrease cardiomyocyte apoptosis induced by H/R. Moreover, miR-141-3p interacts with CHD8. Furthermore, miR-141-3p and CHD8 reduce the expression of p21. Conclusion:MiR-141-3p and CHD8 play critical roles in cardiomyocyte apoptosis induced by H/R. These studies suggest that miR-141-3p and CHD8 mediated cardiomyocyte apoptosis may offer a novel therapeutic strategy against myocardial I/R injury-induced cardiovascular diseases.

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Autism‐linked CHD gene expression patterns during development predict multi‐organ disease phenotypes

Cited by 15 publications

References 99 publications

Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development

Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development

Autism genetics perturb prenatal neurodevelopment through a hierarchy of broadly-expressed and brain-specific genes

Critical roles of microRNA-141-3p and CHD8 in hypoxia/reoxygenation-induced cardiomyocyte apoptosis

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