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The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266032 | GEO | 2025/09/25

REPOSITORIES: GEO

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The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [scMultiome]

Project description:Background/objectives: Deletions and duplications of the distal 1q21.1 region are associated with syndromic forms of autism (MIM612474, 612475). Variable phenotypes have been reported, including congenital heart defects, autism, schizophrenia, head circumference and height defects. Methods: To elucidate which gene(s) are responsible for the 1q21.1 duplication/deletion- associated phenotypes, we performed gene manipulation in zebrafish and mice. We deciphered the function of candidate driver(s) by multi-omics approaches on human iPSC- derived neural progenitor cells (NPC) and cerebral organoids (CO). Results: We modeled duplication of the 1q21.1 region by overexpressing the 8 genes in the region in zebrafish. We found that only overexpression of CHD1L led to macrocephaly and increased larval body length. Conversely, deletion of the CHD1L zebrafish ortholog resulted in microcephaly and decreased larval body length. These mirror phenotypes are also observed when Chd1l expression is modulated in a mammalian model, notably with a variation in the number of mature Tbr1-positive neurons in the mouse embryo. NPCs derived from control and CHD1L Knock-out isogenic hiPSCs were subjected to transcriptomic and chromatin accessibility analyses. These approaches revealed that CHD1L regulates the expression levels and accessibility of genes involved in neuronal differentiation and synaptogenesis, including autism susceptibility genes such as UNC5D and DPP6. Strikingly, absence of CHD1L shifts the cellular identity from forebrain to retinal fate in CO. Finally, pathogenic missense and truncating variants of CHD1L were found in individuals with autism and/or height defects. Conclusion: CHD1L is a major contributor of the 1q21.1 duplication/deletion-associated microcephaly and growth defects. CHD1L dosage is required during human brain regionalization.

2025-09-25 | GSE266031 | GEO

The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [ATAC-seq]

2025-09-25 | GSE266029 | GEO

The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [RNA-seq]

2025-09-25 | GSE266030 | GEO

The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [CUT&RUN]

2025-09-25 | GSE278734 | GEO

The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome.

Project description:The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome.

| PRJNA1105366 | ENA

The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [scMultiome]

Project description:The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [scMultiome]

| PRJNA1105369 | ENA

The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [ATAC-seq]

Project description:The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [ATAC-seq]

| PRJNA1105368 | ENA

The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [CUT&RUN]

Project description:The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [CUT&RUN]

| PRJNA1168533 | ENA

The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [RNA-seq]

Project description:The chromatin remodeler CHD1L controls human cortical neurogenesis and contributes to distal 1q21.1 deletion/duplication syndrome [RNA-seq]

| PRJNA1105370 | ENA

Using induced pluripotent stem cells to investigate human neuronal phenotypes in 1q21.1 deletion and duplication syndrome.

Project description:Copy Number Variation (CNV) at the 1q21.1 locus is associated with a range of neurodevelopmental and psychiatric disorders in humans, including abnormalities in head size and motor deficits. Yet, the functional consequences of these CNVs (both deletion and duplication) on neuronal development remain unknown. To determine the impact of CNV at the 1q21.1 locus on neuronal development, we generated induced pluripotent stem cells from individuals harbouring 1q21.1 deletion or duplication and differentiated them into functional cortical neurons. We show that neurons with 1q21.1 deletion or duplication display reciprocal phenotype with respect to proliferation, differentiation potential, neuronal maturation, synaptic density and functional activity. Deletion of the 1q21.1 locus was also associated with an increased expression of lower cortical layer markers. This difference was conserved in the mouse model of 1q21.1 deletion, which displayed altered corticogenesis. Importantly, we show that neurons with 1q21.1 deletion and duplication are associated with differential expression of calcium channels and demonstrate that physiological deficits in neurons with 1q21.1 deletion or duplication can be pharmacologically modulated by targeting Ca2+ channel activity. These findings provide biological insight into the neuropathological mechanism underlying 1q21.1 associated brain disorder and indicate a potential target for therapeutic interventions.

| S-EPMC9054650 | biostudies-literature

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