---
_id: '11160'
abstract:
- lang: eng
  text: 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.
acknowledged_ssus:
- _id: Bio
- _id: LifeSc
acknowledgement: We thank Farnaz Freeman for technical assistance. This research was
  supported by the Scientific Service Units (SSU) of IST Austria through resources
  provided by the Bioimaging Facility (BIF) and the Life Science Facility (LSF). This
  work supported by the European Union’s Horizon 2020 research and innovation program
  (ERC) grant 715508 to G.N. (REVERSEAUTISM) and grant 825759 to G.T. (ENDpoiNTs);
  the Fondazione Cariplo 2017-0886 to A.L.T.; E-Rare-3 JTC 2018 IMPACT to M. Gabriele;
  and the Austrian Science Fund FWF I 4205-B to G.N. Graphical abstract and figures
  were created using BioRender.com.
article_number: '110615'
article_processing_charge: Yes
article_type: original
author:
- first_name: Carlo Emanuele
  full_name: Villa, Carlo Emanuele
  last_name: Villa
- first_name: Cristina
  full_name: Cheroni, Cristina
  last_name: Cheroni
- first_name: Christoph
  full_name: Dotter, Christoph
  id: 4C66542E-F248-11E8-B48F-1D18A9856A87
  last_name: Dotter
  orcid: 0000-0002-9033-9096
- first_name: Alejandro
  full_name: López-Tóbon, Alejandro
  last_name: López-Tóbon
- first_name: Bárbara
  full_name: Oliveira, Bárbara
  id: 3B03AA1A-F248-11E8-B48F-1D18A9856A87
  last_name: Oliveira
- first_name: Roberto
  full_name: Sacco, Roberto
  id: 42C9F57E-F248-11E8-B48F-1D18A9856A87
  last_name: Sacco
- first_name: Aysan Çerağ
  full_name: Yahya, Aysan Çerağ
  id: 365A65F8-F248-11E8-B48F-1D18A9856A87
  last_name: Yahya
- first_name: Jasmin
  full_name: Morandell, Jasmin
  id: 4739D480-F248-11E8-B48F-1D18A9856A87
  last_name: Morandell
- first_name: Michele
  full_name: Gabriele, Michele
  last_name: Gabriele
- first_name: Mojtaba
  full_name: Tavakoli, Mojtaba
  id: 3A0A06F4-F248-11E8-B48F-1D18A9856A87
  last_name: Tavakoli
  orcid: 0000-0002-7667-6854
- first_name: Julia
  full_name: Lyudchik, Julia
  id: 46E28B80-F248-11E8-B48F-1D18A9856A87
  last_name: Lyudchik
- first_name: Christoph M
  full_name: Sommer, Christoph M
  id: 4DF26D8C-F248-11E8-B48F-1D18A9856A87
  last_name: Sommer
  orcid: 0000-0003-1216-9105
- first_name: Mariano
  full_name: Gabitto, Mariano
  last_name: Gabitto
- first_name: Johann G
  full_name: Danzl, Johann G
  id: 42EFD3B6-F248-11E8-B48F-1D18A9856A87
  last_name: Danzl
  orcid: 0000-0001-8559-3973
- first_name: Giuseppe
  full_name: Testa, Giuseppe
  last_name: Testa
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
citation:
  ama: Villa CE, Cheroni C, Dotter C, et al. CHD8 haploinsufficiency links autism
    to transient alterations in excitatory and inhibitory trajectories. <i>Cell Reports</i>.
    2022;39(1). doi:<a href="https://doi.org/10.1016/j.celrep.2022.110615">10.1016/j.celrep.2022.110615</a>
  apa: Villa, C. E., Cheroni, C., Dotter, C., López-Tóbon, A., Oliveira, B., Sacco,
    R., … Novarino, G. (2022). CHD8 haploinsufficiency links autism to transient alterations
    in excitatory and inhibitory trajectories. <i>Cell Reports</i>. Elsevier. <a href="https://doi.org/10.1016/j.celrep.2022.110615">https://doi.org/10.1016/j.celrep.2022.110615</a>
  chicago: Villa, Carlo Emanuele, Cristina Cheroni, Christoph Dotter, Alejandro López-Tóbon,
    Bárbara Oliveira, Roberto Sacco, Aysan Çerağ Yahya, et al. “CHD8 Haploinsufficiency
    Links Autism to Transient Alterations in Excitatory and Inhibitory Trajectories.”
    <i>Cell Reports</i>. Elsevier, 2022. <a href="https://doi.org/10.1016/j.celrep.2022.110615">https://doi.org/10.1016/j.celrep.2022.110615</a>.
  ieee: C. E. Villa <i>et al.</i>, “CHD8 haploinsufficiency links autism to transient
    alterations in excitatory and inhibitory trajectories,” <i>Cell Reports</i>, vol.
    39, no. 1. Elsevier, 2022.
  ista: Villa CE, Cheroni C, Dotter C, López-Tóbon A, Oliveira B, Sacco R, Yahya AÇ,
    Morandell J, Gabriele M, Tavakoli M, Lyudchik J, Sommer CM, Gabitto M, Danzl JG,
    Testa G, Novarino G. 2022. CHD8 haploinsufficiency links autism to transient alterations
    in excitatory and inhibitory trajectories. Cell Reports. 39(1), 110615.
  mla: Villa, Carlo Emanuele, et al. “CHD8 Haploinsufficiency Links Autism to Transient
    Alterations in Excitatory and Inhibitory Trajectories.” <i>Cell Reports</i>, vol.
    39, no. 1, 110615, Elsevier, 2022, doi:<a href="https://doi.org/10.1016/j.celrep.2022.110615">10.1016/j.celrep.2022.110615</a>.
  short: C.E. Villa, C. Cheroni, C. Dotter, A. López-Tóbon, B. Oliveira, R. Sacco,
    A.Ç. Yahya, J. Morandell, M. Gabriele, M. Tavakoli, J. Lyudchik, C.M. Sommer,
    M. Gabitto, J.G. Danzl, G. Testa, G. Novarino, Cell Reports 39 (2022).
date_created: 2022-04-15T09:03:10Z
date_published: 2022-04-05T00:00:00Z
date_updated: 2024-03-25T23:30:25Z
day: '05'
ddc:
- '570'
department:
- _id: JoDa
- _id: GaNo
doi: 10.1016/j.celrep.2022.110615
ec_funded: 1
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intvolume: '        39'
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keyword:
- General Biochemistry
- Genetics and Molecular Biology
language:
- iso: eng
month: '04'
oa: 1
oa_version: Published Version
pmid: 1
project:
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  call_identifier: H2020
  grant_number: '715508'
  name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo
    and in vitro Models
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  call_identifier: FWF
  grant_number: I04205
  name: Identification of converging Molecular Pathways Across Chromatinopathies as
    Targets for Therapy
publication: Cell Reports
publication_identifier:
  issn:
  - 2211-1247
publication_status: published
publisher: Elsevier
quality_controlled: '1'
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status: public
title: CHD8 haploinsufficiency links autism to transient alterations in excitatory
  and inhibitory trajectories
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 3E5EF7F0-F248-11E8-B48F-1D18A9856A87
volume: 39
year: '2022'
...
---
_id: '12364'
abstract:
- lang: eng
  text: "Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders
    character\x02ized by behavioral symptoms such as problems in social communication
    and interaction, as\r\nwell as repetitive, restricted behaviors and interests.
    These disorders show a high degree\r\nof heritability and hundreds of risk genes
    have been identifed using high throughput\r\nsequencing technologies. This genetic
    heterogeneity has hampered eforts in understanding\r\nthe pathogenesis of ASD
    but at the same time given rise to the concept of convergent\r\nmechanisms. Previous
    studies have identifed that risk genes for ASD broadly converge\r\nonto specifc
    functional categories with transcriptional regulation being one of the biggest\r\ngroups.
    In this thesis, I focus on this subgroup of genes and investigate the gene regulatory\r\nconsequences
    of some of them in the context of neurodevelopment.\r\nFirst, we showed that mutations
    in the ASD and intellectual disability risk gene Setd5 lead\r\nto perturbations
    of gene regulatory programs in early cell fate specifcation. In addition,\r\nadult
    animals display abnormal learning behavior which is mirrored at the transcriptional\r\nlevel
    by altered activity dependent regulation of postsynaptic gene expression. Lastly,\r\nwe
    link the regulatory function of Setd5 to its interaction with the Paf1 and the
    NCoR\r\ncomplex.\r\nSecond, by modeling the heterozygous loss of the top ASD gene
    CHD8 in human cerebral\r\norganoids we demonstrate profound changes in the developmental
    trajectories of both\r\ninhibitory and excitatory neurons using single cell RNA-sequencing.
    While the former\r\nwere generated earlier in CHD8+/- organoids, the generation
    of the latter was shifted to\r\nlater times in favor of a prolonged progenitor
    expansion phase and ultimately increased\r\norganoid size.\r\nFinally, by modeling
    heterozygous mutations for four ASD associated chromatin modifers,\r\nASH1L, KDM6B,
    KMT5B, and SETD5 in human cortical spheroids we show evidence of\r\nregulatory
    convergence across three of those genes. We observe a shift from dorsal cortical\r\nexcitatory
    neuron fates towards partially ventralized cell types resembling cells from the\r\nlateral
    ganglionic eminence. As this project is still ongoing at the time of writing,
    future\r\nexperiments will aim at elucidating the regulatory mechanisms underlying
    this shift with\r\nthe aim of linking these three ASD risk genes through biological
    convergence."
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Christoph
  full_name: Dotter, Christoph
  id: 4C66542E-F248-11E8-B48F-1D18A9856A87
  last_name: Dotter
  orcid: 0000-0002-9033-9096
citation:
  ama: Dotter C. Transcriptional consequences of mutations in genes associated with
    Autism Spectrum Disorder. 2022. doi:<a href="https://doi.org/10.15479/at:ista:12094">10.15479/at:ista:12094</a>
  apa: Dotter, C. (2022). <i>Transcriptional consequences of mutations in genes associated
    with Autism Spectrum Disorder</i>. Institute of Science and Technology Austria.
    <a href="https://doi.org/10.15479/at:ista:12094">https://doi.org/10.15479/at:ista:12094</a>
  chicago: Dotter, Christoph. “Transcriptional Consequences of Mutations in Genes
    Associated with Autism Spectrum Disorder.” Institute of Science and Technology
    Austria, 2022. <a href="https://doi.org/10.15479/at:ista:12094">https://doi.org/10.15479/at:ista:12094</a>.
  ieee: C. Dotter, “Transcriptional consequences of mutations in genes associated
    with Autism Spectrum Disorder,” Institute of Science and Technology Austria, 2022.
  ista: Dotter C. 2022. Transcriptional consequences of mutations in genes associated
    with Autism Spectrum Disorder. Institute of Science and Technology Austria.
  mla: Dotter, Christoph. <i>Transcriptional Consequences of Mutations in Genes Associated
    with Autism Spectrum Disorder</i>. Institute of Science and Technology Austria,
    2022, doi:<a href="https://doi.org/10.15479/at:ista:12094">10.15479/at:ista:12094</a>.
  short: C. Dotter, Transcriptional Consequences of Mutations in Genes Associated
    with Autism Spectrum Disorder, Institute of Science and Technology Austria, 2022.
date_created: 2023-01-24T13:09:57Z
date_published: 2022-09-19T00:00:00Z
date_updated: 2023-11-16T13:10:22Z
day: '19'
ddc:
- '570'
degree_awarded: PhD
department:
- _id: GradSch
- _id: GaNo
doi: 10.15479/at:ista:12094
ec_funded: 1
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language:
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month: '09'
oa: 1
oa_version: Published Version
page: '152'
project:
- _id: 254BA948-B435-11E9-9278-68D0E5697425
  grant_number: '401299'
  name: Probing development and reversibility of autism spectrum disorders
- _id: 9B91375C-BA93-11EA-9121-9846C619BF3A
  grant_number: '707964'
  name: Critical windows and reversibility of ASD associated with mutations in chromatin
    remodelers
- _id: 25444568-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '715508'
  name: Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo
    and in vitro Models
- _id: 2690FEAC-B435-11E9-9278-68D0E5697425
  call_identifier: FWF
  grant_number: I04205
  name: Identification of converging Molecular Pathways Across Chromatinopathies as
    Targets for Therapy
publication_identifier:
  issn:
  - 2663-337X
publication_status: published
publisher: Institute of Science and Technology Austria
related_material:
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  - id: '11160'
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status: public
supervisor:
- first_name: Gaia
  full_name: Novarino, Gaia
  id: 3E57A680-F248-11E8-B48F-1D18A9856A87
  last_name: Novarino
  orcid: 0000-0002-7673-7178
title: Transcriptional consequences of mutations in genes associated with Autism Spectrum
  Disorder
type: dissertation
user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9
year: '2022'
...