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RAI1 safeguards fidelity and tempo of human neurodevelopmental gene expression

ABSTRACT: Human brain development proceeds on an unusually long timeline, fostering the species' cognitive advantages. Retinoic Acid Induced 1 (RAI1) gene encodes a nucleosome-binding protein haploinsufficient in Smith–Magenis Syndrome (SMS), a neurodevelopmental disorder characterized by cognitive deficits with autistic features. However, the role of RAI1 in human neurodevelopment remains unexplored experimentally. Here, we generated isogenic heterozygous and homozygous RAI1 loss-of-function human embryonic stem cell lines and interrogated the roles of RAI1 in neurodevelopmental gene regulation. A longitudinal transcriptome study during in vitro cortical development revealed that RAI1 deficiency accelerates developmental transcriptome progression, as indicated by the induction of synaptic genes. Single-cell RNA-seq analysis revealed that RAI1-deficient neuroprogenitors acquire a transient mesoderm-like gene expression signature followed by pro-neuronal maturation gene expression in postmitotic neurons. Unexpectedly, the developmental acceleration signature was exacerbated during NGN2-induced excitatory neuron differentiation, suggesting functional interplay between RAI1 and NGN2-driven programs. Together, these results identify RAI1 as a suppressor of the mesodermal lineage program and as a novel brake that slows the tempo of human neurodevelopmental gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE337485 | GEO | 2026/07/08

REPOSITORIES: GEO

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RAI1 safeguards fidelity and tempo of human neurodevelopmental gene expression.

Project description:Human brain development proceeds on an unusually long timeline, fostering the species' cognitive advantages. Retinoic Acid Induced 1 (RAI1) gene encodes a nucleosome-binding protein haploinsufficient in Smith–Magenis Syndrome (SMS), a neurodevelopmental disorder characterized by cognitive deficits with autistic features. However, the role of RAI1 in human neurodevelopment remains unexplored experimentally. Here, we generated isogenic heterozygous and homozygous RAI1 loss-of-function human embryonic stem cell lines and interrogated the roles of RAI1 in neurodevelopmental gene regulation. A longitudinal transcriptome study during in vitro cortical development revealed that RAI1 deficiency accelerates developmental transcriptome progression, as indicated by the induction of synaptic genes. Single-cell RNA-seq analysis revealed that RAI1-deficient neuroprogenitors acquire a transient mesoderm-like gene expression signature followed by pro-neuronal maturation gene expression in postmitotic neurons. Unexpectedly, the developmental acceleration signature was exacerbated during NGN2-induced excitatory neuron differentiation, suggesting functional interplay between RAI1 and NGN2-driven programs. Together, these results identify RAI1 as a suppressor of the mesodermal lineage program and as a novel brake that slows the tempo of human neurodevelopmental gene expression.

2026-07-08 | GSE337750 | GEO

RAI1 safeguards fidelity and tempo of human neurodevelopmental gene expression [scRNA-Seq]

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RAI1 safeguards fidelity and tempo of human neurodevelopmental gene expression

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Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics and 3D genomics

Project description:Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances and stereotypic behaviors. We investigated a cohort of 15 individuals with a clinical suspicion of SMS, who showed neither deletion in the SMS critical region nor damaging variants in RAI1. Potentially deleterious variants were identified in nine of these subjects using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of coexpression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1-/- mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1-/- mouse model. These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder.

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Integrating Molecular and Organismal Analyses of Rai1, The Causal Gene for Smith-Magenis Syndrome

Project description:Integrating Molecular and Organismal Analyses of Rai1, The Causal Gene for Smith-Magenis Syndrome

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RNA-Sequencing to identify the transcriptional targets of Rai1

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