---
_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
file:
- access_level: open_access
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  date_created: 2023-01-24T13:15:45Z
  date_updated: 2023-09-20T22:30:03Z
  embargo: 2023-09-19
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has_accepted_license: '1'
language:
- iso: eng
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:
  record:
  - id: '3'
    relation: part_of_dissertation
    status: public
  - id: '11160'
    relation: part_of_dissertation
    status: public
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'
...