CoChat
Sign Up
Cited by 92Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchNeurogenesis and neuroplasticity mechanisms

CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories

Open access
Villa, Carlo Emanuele, Cheroni, Cristina, Dotter, Christoph P., López-Tóbon, Alejandro, Oliveira, Bárbara, Sacco, Roberto, Yahya, Aysan Çerağ, Morandell, Jasmin +8 more·2022·Cell Reports
DOI 10.1016/j.celrep.2022.110615
Open this paper in CoChat — free account

Abstract

Mutations in the chromodomain helicase DNA-binding 8 (CHD8) gene are a frequent cause of autism spectrum disorder (ASD). While its phenotypic spectrum often encompasses macrocephaly, implicating cortical abnormalities, how CHD8 haploinsufficiency affects neurodevelopmental is unclear. Here, employing human cerebral organoids, we find that CHD8 haploinsufficiency disrupted neurodevelopmental trajectories with an accelerated and delayed generation of, respectively, inhibitory and excitatory neurons that yields, at days 60 and 120, symmetrically opposite expansions in their proportions. This imbalance is consistent with an enlargement of cerebral organoids as an in vitro correlate of patients' macrocephaly. Through an isogenic design of patient-specific mutations and mosaic organoids, we define genotype-phenotype relationships and uncover their cell-autonomous nature. Our results define cell-type-specific CHD8-dependent molecular defects related to an abnormal program of proliferation and alternative splicing. By identifying cell-type-specific effects of CHD8 mutations, our study uncovers reproducible developmental alterations that may be employed for neurodevelopmental disease modeling.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2022.110615

Cites

12 of 12 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Effects of perturbations of ASD risk genes on cell-type abundances can sometimes be transient.

    “Additionally, the effects of perturbations of ASD risk genes on cell-type abundances can sometimes be transient11,53, and therefore certain abnormalities during development may not be captured.”

    From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [53]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Part of this paper’s reference list could not be split into single entries.

Flagged first, then by citations

Research works printed but not linked: 58

  1. [2]2. Ardhanareeswaran, K. ∙ Mariani, J. ∙ Coppola, G. ... Human induced pluripotent stem cells for modelling neurodevelopmental disorders Nat. Rev. Neurol. 2017; 13:265-278 Crossref Scopus (121) PubMed Google Scholar
  2. [3]3. Barkas, N. ∙ Petukhov, V. ∙ Nikolaeva, D. ... Joint analysis of heterogeneous single-cell RNA-seq dataset collections Nat. Methods. 2019; 16:695-698 Crossref Scopus (156) PubMed Google Scholar
  3. [4]4. Becht, E. ∙ McInnes, L. ∙ Healy, J. ... Dimensionality reduction for visualizing single-cell data using UMAP Nat. Biotechnol. 2018; 37:38-44 Crossref Scopus (2577) Google Scholar
  4. [5]5. Beighley, J.S. ∙ Hudac, C.M. ∙ Arnett, A.B. ... Clinical phenotypes of carriers of mutations in CHD8 or its conserved target genes Biol. Psychiatry. 2020; 87:123-131 Full Text Full Text (PDF) Scopus (22) PubMed Google Scholar
  5. [6]6. Benito-Kwiecinski, S. ∙ Giandomenico, S.L. ∙ Sutcliffe, M. ... An early cell shape transition drives evolutionary expansion of the human forebrain Cell. 2020; 184:2084-2102 Full Text Full Text (PDF) Scopus (140) Google Scholar
  6. [7]7. Bernier, R. ∙ Golzio, C. ∙ Xiong, B. ... Disruptive CHD8 mutations define a subtype of autism early in development Cell. 2014; 158:263-276 Full Text Full Text (PDF) Scopus (540) PubMed Google Scholar
  7. [8]8. Birey, F. ∙ Li, M.Y. ∙ Gordon, A. ... Dissecting the molecular basis of human interneuron migration in forebrain assembloids from Timothy syndrome Cell Stem Cell. 2021; 29:248-264.e7 Full Text Full Text (PDF) Scopus (64) Google Scholar
  8. [9]9. Bohnsack, K.E. ∙ Bohnsack, M.T. Uncovering the assembly pathway of human ribosomes and its emerging links to disease EMBO J. 2019; 38:e100278 Crossref Scopus (138) PubMed Google Scholar
  9. [10]10. Cagnetta, R. ∙ Wong, H.H. ∙ Frese, C.K. ... Noncanonical modulation of the eIF2 pathway controls an increase in local translation during neural wiring Mol. Cell. 2019; 73:474-489.e475 Full Text Full Text (PDF) Scopus (65) PubMed Google Scholar
  10. [11]11. Camp, J.G. ∙ Badsha, F. ∙ Florio, M. ... Human cerebral organoids recapitulate gene expression programs of fetal neocortex development Proc. Natl. Acad. Sci. U S A. 2015; 112:15672-15677 Crossref Scopus (105) PubMed Google Scholar
  11. [12]12. Catlett, T.S. ∙ Onesto, M.M. ∙ McCann, A.J. ... RHOA signaling defects result in impaired axon guidance in iPSC-derived neurons from patients with tuberous sclerosis complex Nat. Commun. 2021; 12:2589 Crossref Scopus (18) PubMed Google Scholar
  12. [13]13. Chen, E.S. ∙ Gigek, C.O. ∙ Rosenfeld, J.A. ... Molecular convergence of neurodevelopmental disorders Am. J. Hum. Genet. 2014; 95:490-508 Full Text Full Text (PDF) Scopus (57) PubMed Google Scholar
  13. [14]14. Chen, H. ∙ Albergante, L. ∙ Hsu, J.Y. ... Single-cell trajectories reconstruction, exploration and mapping of omics data with STREAM Nat. Commun. 2019; 10:1903 Crossref Scopus (164) PubMed Google Scholar
  14. [15]15. Concordet, J.P. ∙ Haeussler, M. CRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens Nucleic Acids Res. 2018; 46:W242-W245 Crossref Scopus (962) PubMed Google Scholar
  15. [16]16. Cotney, J. ∙ Muhle, R.A. ∙ Sanders, S.J. ... The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment Nat. Commun. 2015; 6:6404 Crossref Scopus (231) PubMed Google Scholar
  16. [17]17. de Jong, J.O. ∙ Llapashtica, C. ∙ Genestine, M. ... Cortical overgrowth in a preclinical forebrain organoid model of CNTNAP2-associated autism spectrum disorder Nat. Commun. 2021; 12:4087 Crossref Scopus (47) PubMed Google Scholar
  17. [19]19. Dehghannasiri, R. ∙ Olivieri, J.E. ∙ Damljanovic, A. ... Specific splice junction detection in single cells with Sicilian Genome Biol. 2021; 22:219 Crossref Scopus (10) PubMed Google Scholar
  18. [20]20. Dobin, A. ∙ Davis, C.A. ∙ Schlesinger, F. ... STAR: ultrafast universal RNA-seq aligner Bioinformatics. 2013; 29:15-21 Crossref Scopus (27042) PubMed Google Scholar
  19. [22]22. Falcon, S. ∙ Gentleman, R. Using GOstats to test gene lists for GO term association Bioinformatics. 2007; 23:257-258 Crossref Scopus (1502) PubMed Google Scholar
  20. [26]26. Hanly, C. ∙ Shah, H. ∙ Au, P.Y.B. ... Description of neurodevelopmental phenotypes associated with 10 genetic neurodevelopmental disorders: a scoping review Clin. Genet. 2020; 99:335-346 Crossref Scopus (34) PubMed Google Scholar
  21. [27]27. Heinz, S. ∙ Benner, C. ∙ Spann, N. ... Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities Mol. Cell. 2010; 38:576-589 Full Text Full Text (PDF) Scopus (8020) PubMed Google Scholar
  22. [29]29. Kachaev, Z.M. ∙ Ivashchenko, S.D. ∙ Kozlov, E.N. ... Localization and functional roles of components of the translation apparatus in the eukaryotic cell nucleus Cells. 2021; 10:3239 Crossref Scopus (8) PubMed Google Scholar
  23. [30]30. Katayama, Y. ∙ Nishiyama, M. ∙ Shoji, H. ... CHD8 haploinsufficiency results in autistic-like phenotypes in mice Nature. 2016; 537:675-679 Crossref Scopus (230) PubMed Google Scholar
  24. [31]31. Kuleshov, M.V. ∙ Jones, M.R. ∙ Rouillard, A.D. ... Enrichr: a comprehensive gene set enrichment analysis web server 2016 update Nucleic Acids Res. 2016; 44:W90-W97 Crossref Scopus (5603) PubMed Google Scholar
  25. [32]32. Lancaster, M.A. ∙ Knoblich, J.A. Generation of cerebral organoids from human pluripotent stem cells Nat. Protoc. 2014; 9:2329-2340 Crossref Scopus (1058) PubMed Google Scholar
  26. [33]33. Legido, A. ∙ Jethva, R. ∙ Goldenthal, M.J. Mitochondrial dysfunction in autism Semin. Pediatr. Neurol. 2013; 20:163-175 Crossref Scopus (83) PubMed Google Scholar
  27. [34]34. Li, K. ∙ Ouyang, Z. ∙ Lin, D. ... Cellxgene VIP unleashes full power of interactive visualization, plotting and analysis of scRNA-seq data in the scale of millions of cells Preprint at bioRxiv. 2020; 2020.2008.2028.270652 Google Scholar
  28. [35]35. Lopez-Tobon, A. ∙ Villa, C.E. ∙ Cheroni, C. ... Human cortical organoids expose a differential function of GSK3 on cortical neurogenesis Stem Cell Rep. 2019; 13:847-861 Full Text Full Text (PDF) Scopus (36) PubMed Google Scholar
  29. [36]36. Lotfollahi, M. ∙ Wolf, F.A. ∙ Theis, F.J. scGen predicts single-cell perturbation responses Nat. Methods. 2019; 16:715-721 Crossref Scopus (210) PubMed Google Scholar
  30. [37]37. Love, M.I. ∙ Huber, W. ∙ Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol. 2014; 15:550 Crossref Scopus (48397) PubMed Google Scholar
  31. [38]38. Luo, C. ∙ Lancaster, M.A. ∙ Castanon, R. ... Cerebral organoids recapitulate epigenomic signatures of the human fetal brain Cell Rep. 2016; 17:3369-3384 Full Text Full Text (PDF) Scopus (249) PubMed Google Scholar
  32. [39]39. Mariani, J. ∙ Coppola, G. ∙ Zhang, P. ... FOXG1-Dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders Cell. 2015; 162:375-390 Full Text Full Text (PDF) Scopus (794) PubMed Google Scholar
  33. [40]40. Monaghan, C.E. ∙ Nechiporuk, T. ∙ Jeng, S. ... REST corepressors RCOR1 and RCOR2 and the repressor INSM1 regulate the proliferation-differentiation balance in the developing brain Proc. Natl. Acad. Sci. U S A. 2017; 114:E406-E415 Crossref Scopus (47) PubMed Google Scholar
  34. [41]41. Moore, J.C. ∙ Atze, K. ∙ Yeung, P.L. ... Efficient, high-throughput transfection of human embryonic stem cells Stem Cell Res. Ther. 2010; 1:23 Crossref Scopus (49) PubMed Google Scholar
  35. [42]42. Nowakowski, T.J. ∙ Bhaduri, A. ∙ Pollen, A.A. ... Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex Science. 2017; 358:1318-1323 Crossref Scopus (563) PubMed Google Scholar
  36. [43]43. O'Roak, B.J. ∙ Vives, L. ∙ Fu, W. ... Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders Science. 2012; 338:1619-1622 Crossref Scopus (986) PubMed Google Scholar
  37. [45]45. Olivieri, J.E. ∙ Dehghannasiri, R. ∙ Salzman, J. The spliZ generalizes “percent spliced In” to reveal regulated splicing at single-cell resolution Nat. Methods. 2021; 19:307-310 Crossref Scopus (11) Google Scholar
  38. [46]46. Parikshak, N.N. ∙ Luo, R. ∙ Zhang, A. ... Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism Cell. 2013; 155:1008-1021 Full Text Full Text (PDF) Scopus (732) PubMed Google Scholar
  39. [47]47. Pollen, A.A. ∙ Bhaduri, A. ∙ Andrews, M.G. ... Establishing cerebral organoids as models of human-specific brain evolution Cell. 2019; 176:743-756.e717 Full Text Full Text (PDF) Scopus (356) PubMed Google Scholar
  40. [50]50. Rajewsky, N. ∙ Almouzni, G. ∙ Gorski, S.A. ... LifeTime and improving European healthcare through cell-based interceptive medicine Nature. 2020; 587:377-386 Crossref Scopus (96) PubMed Google Scholar
  41. [51]51. Ran, F.A. ∙ Hsu, P.D. ∙ Lin, C.Y. ... Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity Cell. 2013; 154:1380-1389 Full Text Full Text (PDF) Scopus (2632) PubMed Google Scholar
  42. [52]52. Ran, F.A. ∙ Hsu, P.D. ∙ Wright, J. ... Genome engineering using the CRISPR-Cas9 system Nat. Protoc. 2013; 8:2281-2308 Crossref Scopus (7783) PubMed Google Scholar
  43. [54]54. Schindelin, J. ∙ Arganda-Carreras, I. ∙ Frise, E. ... Fiji: an open-source platform for biological-image analysis Nat. Methods. 2012; 9:676-682 Crossref Scopus (39955) PubMed Google Scholar
  44. [56]56. Srivastava, A. ∙ Malik, L. ∙ Smith, T. ... Alevin efficiently estimates accurate gene abundances from dscRNA-seq data Genome Biol. 2019; 20:65 Crossref Scopus (126) PubMed Google Scholar
  45. [57]57. Stamova, B.S. ∙ Tian, Y. ∙ Nordahl, C.W. ... Evidence for differential alternative splicing in blood of young boys with autism spectrum disorders Mol. Autism. 2013; 4:30 Crossref Scopus (52) PubMed Google Scholar
  46. [58]58. Stringer, C. ∙ Wang, T. ∙ Michaelos, M. ... Cellpose: a generalist algorithm for cellular segmentation Preprint at bioRxiv. 2020; 2020.2002.2002.931238 Google Scholar
  47. [59]59. Suetterlin, P. ∙ Hurley, S. ∙ Mohan, C. ... Altered neocortical gene expression, brain overgrowth and functional over-connectivity in Chd8 haploinsufficient mice Cereb. Cortex. 2018; 28:2192-2206 Crossref Scopus (81) PubMed Google Scholar
  48. [60]60. Sugathan, A. ∙ Biagioli, M. ∙ Golzio, C. ... CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors Proc. Natl. Acad. Sci. U S A. 2014; 111:E4468-E4477 Crossref Scopus (237) PubMed Google Scholar
  49. [61]61. Thompson, B.A. ∙ Tremblay, V. ∙ Lin, G. ... CHD8 is an ATP-dependent chromatin remodeling factor that regulates beta-catenin target genes Mol. Cell Biol. 2008; 28:3894-3904 Crossref Scopus (162) PubMed Google Scholar
  50. [62]62. Tomoiaga, D. ∙ Aguiar-Pulido, V. ∙ Shrestha, S. ... Single-cell sperm transcriptomes and variants from fathers of children with and without autism spectrum disorder NPJ Genom Med. 2020; 5:14 Crossref Scopus (12) PubMed Google Scholar
  51. [63]63. Traag, V.A. ∙ Waltman, L. ∙ van Eck, N.J. From Louvain to Leiden: guaranteeing well-connected communities Sci. Rep. 2019; 9:5233 Crossref Scopus (1915) PubMed Google Scholar
  52. [64]64. Trincado, J.L. ∙ Entizne, J.C. ∙ Hysenaj, G. ... SUPPA2: fast, accurate, and uncertainty-aware differential splicing analysis across multiple conditions Genome Biol. 2018; 19:40 Crossref Scopus (321) PubMed Google Scholar
  53. [65]65. Urresti, J. ∙ Zhang, P. ∙ Moran-Losada, P. ... Cortical organoids model early brain development disrupted by 16p11.2 copy number variants in autism Mol. Psychiatry. 2021; 26:7560-7580 Crossref Scopus (57) PubMed Google Scholar
  54. [66]66. Wang, E.T. ∙ Sandberg, R. ∙ Luo, S. ... Alternative isoform regulation in human tissue transcriptomes Nature. 2008; 456:470-476 Crossref Scopus (3905) PubMed Google Scholar
  55. [67]67. Wang, P. ∙ Lin, M. ∙ Pedrosa, E. ... CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in neurodevelopment Mol. Autism. 2015; 6:55 Crossref Scopus (115) PubMed Google Scholar
  56. [68]68. Wang, P. ∙ Mokhtari, R. ∙ Pedrosa, E. ... CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells Mol. Autism. 2017; 8:11 Crossref Scopus (191) PubMed Google Scholar
  57. [69]69. Wegscheid, M.L. ∙ Anastasaki, C. ∙ Hartigan, K.A. ... Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis Cell Rep. 2021; 36:109315 Full Text Full Text (PDF) Scopus (28) PubMed Google Scholar
  58. [71]71. Willsey, A.J. ∙ Sanders, S.J. ∙ Li, M. ... Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism Cell. 2013; 155:997-1007 Full Text Full Text (PDF) Scopus (649) PubMed Google Scholar

Cited by

Sorted by citations

Authors
Villa, C. E., Cheroni, C., Dotter, C. P., López-Tóbon, A., Oliveira, B., Sacco, R., Yahya, A. Ç., Morandell, J., Gabriele, M., Tavakoli, M. R., Lyudchik, J., Sommer, C., Gabitto, M., Danzl, J. G., Testa, G., & Novarino, G.
Affiliations
  • Human Technopole (IT)
  • University of Milan (IT)
  • Institute of Science and Technology Austria (AT)
  • European Institute of Oncology (IT)
  • Allen Institute for Brain Science (US)
Corresponding author
  • Testa, Giuseppe
  • Novarino, Gaia
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2022-04
Volume
39
Issue
1
Pages
110615
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2022.110615
OpenAlex
W4223506312
Cited by
92
References
12
Citations by year
2026: 14 · 2025: 25 · 2024: 18 · 2023: 21 · 2022: 14
FWCI
11.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Horizon 2020
  • Horizon 2020 Framework Programme (825759)
  • European Research Council (715508)
  • Austrian Science Fund (I 4205-B)
  • Fondazione Cariplo (2017-0886, E-Rare-3 JTC 2018 IMPACT)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
CHD8, haploinsufficiency, autism spectrum disorder, brain organoids, excitatory and inhibitory neurons, macrocephaly, brain development, genotype-phenotype correlation, alternative splicing, cell proliferation
MeSH terms
Autism Spectrum Disorder, Autistic Disorder, DNA Helicases, DNA-Binding Proteins, Humans, Transcription Factors, Haploinsufficiency, Megalencephaly

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review