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The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.

Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP - Nat Commun (2015)

Bottom Line: CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8.Integration of CHD8-binding data into ASD risk models improves detection of risk genes.These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Genetics, Yale School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA [2] Kavli Institute for Neuroscience, Yale School of Medicine, PO Box 208001, New Haven, Connecticut 06520, USA.

ABSTRACT
Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human midfetal cortex, suggesting that ASD risk genes converge in specific regulatory networks during neurodevelopment. To elucidate such networks, we identify genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex. CHD8 targets are strongly enriched for other ASD risk genes in both human and mouse neurodevelopment, and converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8. Integration of CHD8-binding data into ASD risk models improves detection of risk genes. These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development.

No MeSH data available.


Related in: MedlinePlus

Depletion of CHD8 in hNSCs significantly affects ASD risk genes.(a) Mean differential expression P values for ASD risk genes from Liu et al. or Willsey et al. bound by CHD8 versus other genes bound by CHD8 but not in the respective ASD risk gene list. The significance of differences between mean differential expression P-values across gene sets was assessed using Wilcoxon rank tests. Note that CHD8 targets in Liu et al. are significantly dysregulated compared with other CHD8 targets in both knockdowns, whereas CHD8 targets in Willsey et al. are significantly dysregulated compared with other targets only in knockdown C. (b) Scatterplot of log2 fold change gene expression values and log2 read counts per million (CPM) for genes strongly dysregulated in hNSCs transfected with shRNA target C, as compared with scrambled control (EdgeR Poisson P value<1.68 × 10−6 and absolute log2 fold change>0.1, and log2(CPM) between 2 and 10). CHD8 is indicated by a red circle. ASD risk genes from Liu et al. are indicated by purple dots.
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f5: Depletion of CHD8 in hNSCs significantly affects ASD risk genes.(a) Mean differential expression P values for ASD risk genes from Liu et al. or Willsey et al. bound by CHD8 versus other genes bound by CHD8 but not in the respective ASD risk gene list. The significance of differences between mean differential expression P-values across gene sets was assessed using Wilcoxon rank tests. Note that CHD8 targets in Liu et al. are significantly dysregulated compared with other CHD8 targets in both knockdowns, whereas CHD8 targets in Willsey et al. are significantly dysregulated compared with other targets only in knockdown C. (b) Scatterplot of log2 fold change gene expression values and log2 read counts per million (CPM) for genes strongly dysregulated in hNSCs transfected with shRNA target C, as compared with scrambled control (EdgeR Poisson P value<1.68 × 10−6 and absolute log2 fold change>0.1, and log2(CPM) between 2 and 10). CHD8 is indicated by a red circle. ASD risk genes from Liu et al. are indicated by purple dots.

Mentions: Finally, we evaluated the effect of CHD8 knockdown on the two sets of ASD risk genes described above. These genes are significantly overrepresented only in CHD8 targets that are shared across multiple neurodevelopmental targets, which is the same CHD8 target set most impacted by CHD8 knockdown and with the greatest CHD8-binding signal. In light of these results, we hypothesized that ASD risk gene expression would be disproportionately affected by CHD8 knockdown compared with other CHD8 gene targets in hNSCs. The overall effect of CHD8 loss on the expression of both sets of genes was generally consistent, in that they were significantly perturbed as a group in at least one knockdown (Supplementary Data 7). Strikingly, we observed that ASD risk genes whose promoters are bound by CHD8 in hNSCs appear to be more significantly dysregulated than other CHD8 targets in these cells. (Fig. 5a). When we considered genes that showed the strongest dysregulation due to CHD8 knockdown, we found that ASD risk genes tended to be downregulated (Fig. 5b). These results, coupled with the co-occurrence of activating chromatin marks at CHD8-bound promoters, suggest CHD8 directly influences the activation of other ASD risk genes in human neurodevelopment.


The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment.

Cotney J, Muhle RA, Sanders SJ, Liu L, Willsey AJ, Niu W, Liu W, Klei L, Lei J, Yin J, Reilly SK, Tebbenkamp AT, Bichsel C, Pletikos M, Sestan N, Roeder K, State MW, Devlin B, Noonan JP - Nat Commun (2015)

Depletion of CHD8 in hNSCs significantly affects ASD risk genes.(a) Mean differential expression P values for ASD risk genes from Liu et al. or Willsey et al. bound by CHD8 versus other genes bound by CHD8 but not in the respective ASD risk gene list. The significance of differences between mean differential expression P-values across gene sets was assessed using Wilcoxon rank tests. Note that CHD8 targets in Liu et al. are significantly dysregulated compared with other CHD8 targets in both knockdowns, whereas CHD8 targets in Willsey et al. are significantly dysregulated compared with other targets only in knockdown C. (b) Scatterplot of log2 fold change gene expression values and log2 read counts per million (CPM) for genes strongly dysregulated in hNSCs transfected with shRNA target C, as compared with scrambled control (EdgeR Poisson P value<1.68 × 10−6 and absolute log2 fold change>0.1, and log2(CPM) between 2 and 10). CHD8 is indicated by a red circle. ASD risk genes from Liu et al. are indicated by purple dots.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4355952&req=5

f5: Depletion of CHD8 in hNSCs significantly affects ASD risk genes.(a) Mean differential expression P values for ASD risk genes from Liu et al. or Willsey et al. bound by CHD8 versus other genes bound by CHD8 but not in the respective ASD risk gene list. The significance of differences between mean differential expression P-values across gene sets was assessed using Wilcoxon rank tests. Note that CHD8 targets in Liu et al. are significantly dysregulated compared with other CHD8 targets in both knockdowns, whereas CHD8 targets in Willsey et al. are significantly dysregulated compared with other targets only in knockdown C. (b) Scatterplot of log2 fold change gene expression values and log2 read counts per million (CPM) for genes strongly dysregulated in hNSCs transfected with shRNA target C, as compared with scrambled control (EdgeR Poisson P value<1.68 × 10−6 and absolute log2 fold change>0.1, and log2(CPM) between 2 and 10). CHD8 is indicated by a red circle. ASD risk genes from Liu et al. are indicated by purple dots.
Mentions: Finally, we evaluated the effect of CHD8 knockdown on the two sets of ASD risk genes described above. These genes are significantly overrepresented only in CHD8 targets that are shared across multiple neurodevelopmental targets, which is the same CHD8 target set most impacted by CHD8 knockdown and with the greatest CHD8-binding signal. In light of these results, we hypothesized that ASD risk gene expression would be disproportionately affected by CHD8 knockdown compared with other CHD8 gene targets in hNSCs. The overall effect of CHD8 loss on the expression of both sets of genes was generally consistent, in that they were significantly perturbed as a group in at least one knockdown (Supplementary Data 7). Strikingly, we observed that ASD risk genes whose promoters are bound by CHD8 in hNSCs appear to be more significantly dysregulated than other CHD8 targets in these cells. (Fig. 5a). When we considered genes that showed the strongest dysregulation due to CHD8 knockdown, we found that ASD risk genes tended to be downregulated (Fig. 5b). These results, coupled with the co-occurrence of activating chromatin marks at CHD8-bound promoters, suggest CHD8 directly influences the activation of other ASD risk genes in human neurodevelopment.

Bottom Line: CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8.Integration of CHD8-binding data into ASD risk models improves detection of risk genes.These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Genetics, Yale School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA [2] Kavli Institute for Neuroscience, Yale School of Medicine, PO Box 208001, New Haven, Connecticut 06520, USA.

ABSTRACT
Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human midfetal cortex, suggesting that ASD risk genes converge in specific regulatory networks during neurodevelopment. To elucidate such networks, we identify genes targeted by CHD8, a chromodomain helicase strongly associated with ASD, in human midfetal brain, human neural stem cells (hNSCs) and embryonic mouse cortex. CHD8 targets are strongly enriched for other ASD risk genes in both human and mouse neurodevelopment, and converge in ASD-associated co-expression networks in human midfetal cortex. CHD8 knockdown in hNSCs results in dysregulation of ASD risk genes directly targeted by CHD8. Integration of CHD8-binding data into ASD risk models improves detection of risk genes. These results suggest loss of CHD8 contributes to ASD by perturbing an ancient gene regulatory network during human brain development.

No MeSH data available.


Related in: MedlinePlus