[{"project":[{"_id":"25444568-B435-11E9-9278-68D0E5697425","call_identifier":"H2020","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","grant_number":"715508"},{"grant_number":"I04205","name":"Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy","call_identifier":"FWF","_id":"2690FEAC-B435-11E9-9278-68D0E5697425"}],"acknowledged_ssus":[{"_id":"Bio"},{"_id":"LifeSc"}],"oa_version":"Published Version","article_number":"110615","month":"04","has_accepted_license":"1","publication":"Cell Reports","keyword":["General Biochemistry","Genetics and Molecular Biology"],"language":[{"iso":"eng"}],"publication_identifier":{"issn":["2211-1247"]},"oa":1,"tmp":{"legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode","short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)"},"type":"journal_article","date_published":"2022-04-05T00:00:00Z","file":[{"file_id":"11164","creator":"dernst","access_level":"open_access","success":1,"relation":"main_file","date_updated":"2022-04-15T09:06:25Z","content_type":"application/pdf","file_name":"2022_CellReports_Villa.pdf","date_created":"2022-04-15T09:06:25Z","file_size":"7808644","checksum":"b4e8d68f0268dec499af333e6fd5d8e1"}],"related_material":{"record":[{"status":"public","id":"12364","relation":"dissertation_contains"}]},"status":"public","user_id":"3E5EF7F0-F248-11E8-B48F-1D18A9856A87","department":[{"_id":"JoDa"},{"_id":"GaNo"}],"date_created":"2022-04-15T09:03:10Z","article_processing_charge":"Yes","publication_status":"published","intvolume":"        39","title":"CHD8 haploinsufficiency links autism to transient alterations in excitatory and inhibitory trajectories","_id":"11160","pmid":1,"issue":"1","author":[{"last_name":"Villa","first_name":"Carlo Emanuele","full_name":"Villa, Carlo Emanuele"},{"full_name":"Cheroni, Cristina","last_name":"Cheroni","first_name":"Cristina"},{"first_name":"Christoph","last_name":"Dotter","orcid":"0000-0002-9033-9096","full_name":"Dotter, Christoph","id":"4C66542E-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Alejandro","last_name":"López-Tóbon","full_name":"López-Tóbon, Alejandro"},{"id":"3B03AA1A-F248-11E8-B48F-1D18A9856A87","full_name":"Oliveira, Bárbara","last_name":"Oliveira","first_name":"Bárbara"},{"full_name":"Sacco, Roberto","first_name":"Roberto","last_name":"Sacco","id":"42C9F57E-F248-11E8-B48F-1D18A9856A87"},{"last_name":"Yahya","first_name":"Aysan Çerağ","full_name":"Yahya, Aysan Çerağ","id":"365A65F8-F248-11E8-B48F-1D18A9856A87"},{"id":"4739D480-F248-11E8-B48F-1D18A9856A87","full_name":"Morandell, Jasmin","last_name":"Morandell","first_name":"Jasmin"},{"last_name":"Gabriele","first_name":"Michele","full_name":"Gabriele, Michele"},{"last_name":"Tavakoli","first_name":"Mojtaba","full_name":"Tavakoli, Mojtaba","orcid":"0000-0002-7667-6854","id":"3A0A06F4-F248-11E8-B48F-1D18A9856A87"},{"first_name":"Julia","last_name":"Lyudchik","full_name":"Lyudchik, Julia","id":"46E28B80-F248-11E8-B48F-1D18A9856A87"},{"id":"4DF26D8C-F248-11E8-B48F-1D18A9856A87","first_name":"Christoph M","last_name":"Sommer","orcid":"0000-0003-1216-9105","full_name":"Sommer, Christoph M"},{"last_name":"Gabitto","first_name":"Mariano","full_name":"Gabitto, Mariano"},{"id":"42EFD3B6-F248-11E8-B48F-1D18A9856A87","last_name":"Danzl","first_name":"Johann G","full_name":"Danzl, Johann G","orcid":"0000-0001-8559-3973"},{"last_name":"Testa","first_name":"Giuseppe","full_name":"Testa, Giuseppe"},{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","last_name":"Novarino","first_name":"Gaia","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178"}],"publisher":"Elsevier","article_type":"original","quality_controlled":"1","ec_funded":1,"file_date_updated":"2022-04-15T09:06:25Z","day":"05","doi":"10.1016/j.celrep.2022.110615","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."}],"year":"2022","citation":{"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).","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>.","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.","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."},"date_updated":"2024-03-25T23:30:25Z","external_id":{"pmid":["35385734"],"isi":["000785983900003"]},"isi":1,"volume":39,"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.","ddc":["570"]},{"has_accepted_license":"1","month":"09","oa_version":"Published Version","project":[{"_id":"254BA948-B435-11E9-9278-68D0E5697425","grant_number":"401299","name":"Probing development and reversibility of autism spectrum disorders"},{"name":"Critical windows and reversibility of ASD associated with mutations in chromatin remodelers","grant_number":"707964","_id":"9B91375C-BA93-11EA-9121-9846C619BF3A"},{"grant_number":"715508","name":"Probing the Reversibility of Autism Spectrum Disorders by Employing in vivo and in vitro Models","_id":"25444568-B435-11E9-9278-68D0E5697425","call_identifier":"H2020"},{"call_identifier":"FWF","_id":"2690FEAC-B435-11E9-9278-68D0E5697425","grant_number":"I04205","name":"Identification of converging Molecular Pathways Across Chromatinopathies as Targets for Therapy"}],"language":[{"iso":"eng"}],"date_published":"2022-09-19T00:00:00Z","type":"dissertation","supervisor":[{"id":"3E57A680-F248-11E8-B48F-1D18A9856A87","last_name":"Novarino","first_name":"Gaia","full_name":"Novarino, Gaia","orcid":"0000-0002-7673-7178"}],"oa":1,"publication_identifier":{"issn":["2663-337X"]},"related_material":{"record":[{"relation":"part_of_dissertation","id":"3","status":"public"},{"status":"public","relation":"part_of_dissertation","id":"11160"}]},"status":"public","user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9","file":[{"access_level":"open_access","relation":"main_file","creator":"cchlebak","file_id":"12365","checksum":"896f4cac9adb6d3f26a6605772f4e1a3","file_size":20457465,"embargo":"2023-09-19","date_created":"2023-01-24T13:15:45Z","content_type":"application/pdf","file_name":"220923_Thesis_CDotter_Final.pdf","date_updated":"2023-09-20T22:30:03Z"},{"access_level":"closed","relation":"source_file","creator":"cchlebak","file_id":"12482","checksum":"ad01bb20da163be6893b7af832e58419","file_size":22433512,"embargo_to":"open_access","date_created":"2023-02-02T09:15:35Z","file_name":"latex_source_CDotter_Thesis_2022.zip","content_type":"application/x-zip-compressed","date_updated":"2023-09-20T22:30:03Z"}],"author":[{"orcid":"0000-0002-9033-9096","full_name":"Dotter, Christoph","first_name":"Christoph","last_name":"Dotter","id":"4C66542E-F248-11E8-B48F-1D18A9856A87"}],"_id":"12364","alternative_title":["ISTA Thesis"],"title":"Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder","publication_status":"published","department":[{"_id":"GradSch"},{"_id":"GaNo"}],"date_created":"2023-01-24T13:09:57Z","article_processing_charge":"No","file_date_updated":"2023-09-20T22:30:03Z","page":"152","ec_funded":1,"publisher":"Institute of Science and Technology Austria","date_updated":"2023-11-16T13:10:22Z","year":"2022","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.","short":"C. Dotter, Transcriptional Consequences of Mutations in Genes Associated with Autism Spectrum Disorder, Institute of Science and Technology Austria, 2022.","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>.","ista":"Dotter C. 2022. Transcriptional consequences of mutations in genes associated with Autism Spectrum Disorder. Institute of Science and Technology Austria."},"abstract":[{"lang":"eng","text":"Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders character\u0002ized 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."}],"doi":"10.15479/at:ista:12094","degree_awarded":"PhD","day":"19","ddc":["570"]}]