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1.
bioRxiv ; 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38187634

RESUMO

Recent studies have identified over one hundred high-confidence (hc) autism spectrum disorder (ASD) genes. Systems biological and functional analyses on smaller subsets of these genes have consistently implicated excitatory neurogenesis. However, the extent to which the broader set of hcASD genes are involved in this process has not been explored systematically nor have the biological pathways underlying this convergence been identified. Here, we leveraged CROP-Seq to repress 87 hcASD genes in a human in vitro model of cortical neurogenesis. We identified 17 hcASD genes whose repression significantly alters developmental trajectory and results in a common cellular state characterized by disruptions in proliferation, differentiation, cell cycle, microtubule biology, and RNA-binding proteins (RBPs). We also characterized over 3,000 differentially expressed genes, 286 of which had expression profiles correlated with changes in developmental trajectory. Overall, we uncovered transcriptional disruptions downstream of hcASD gene perturbations, correlated these disruptions with distinct differentiation phenotypes, and reinforced neurogenesis, microtubule biology, and RBPs as convergent points of disruption in ASD.

2.
bioRxiv ; 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38076945

RESUMO

Translating high-confidence (hc) autism spectrum disorder (ASD) genes into viable treatment targets remains elusive. We constructed a foundational protein-protein interaction (PPI) network in HEK293T cells involving 100 hcASD risk genes, revealing over 1,800 PPIs (87% novel). Interactors, expressed in the human brain and enriched for ASD but not schizophrenia genetic risk, converged on protein complexes involved in neurogenesis, tubulin biology, transcriptional regulation, and chromatin modification. A PPI map of 54 patient-derived missense variants identified differential physical interactions, and we leveraged AlphaFold-Multimer predictions to prioritize direct PPIs and specific variants for interrogation in Xenopus tropicalis and human forebrain organoids. A mutation in the transcription factor FOXP1 led to reconfiguration of DNA binding sites and altered development of deep cortical layer neurons in forebrain organoids. This work offers new insights into molecular mechanisms underlying ASD and describes a powerful platform to develop and test therapeutic strategies for many genetically-defined conditions.

3.
Neuron ; 109(5): 788-804.e8, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33497602

RESUMO

Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Córtex Cerebral/crescimento & desenvolvimento , Estrogênios/fisiologia , Neurogênese , Animais , Transtorno do Espectro Autista/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Avaliação Pré-Clínica de Medicamentos , Estrogênios/administração & dosagem , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Fatores de Risco , Transdução de Sinais , Xenopus
4.
Blood Adv ; 4(13): 2899-2911, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32589729

RESUMO

Cancer cells commonly develop resistance to immunotherapy by loss of antigen expression. Combinatorial treatments that increase levels of the target antigen on the surface of cancer cells have the potential to restore efficacy to immunotherapy. Here, we use our CRISPR interference- and CRISPR activation-based functional genomics platform to systematically identify pathways controlling cell surface expression of the multiple myeloma immunotherapy antigen B-cell maturation antigen (BCMA). We discovered that pharmacologic inhibition of HDAC7 and the Sec61 complex increased cell surface BCMA, including in primary patient cells. Pharmacologic Sec61 inhibition enhanced the antimyeloma efficacy of a BCMA-targeted antibody-drug conjugate. A CRISPR interference chimeric antigen receptor T cells (CAR-T cells) coculture screen enabled us to identify both antigen-dependent and antigen-independent mechanisms controlling response of myeloma cells to BCMA-targeted CAR-T cells. Thus, our study shows the potential of CRISPR screens to uncover mechanisms controlling response of cancer cells to immunotherapy and to suggest potential combination therapies.


Assuntos
Antígeno de Maturação de Linfócitos B , Mieloma Múltiplo , Antígeno de Maturação de Linfócitos B/genética , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos , Imunoterapia , Imunoterapia Adotiva , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Linfócitos T
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