Distal 1q21.1 deletions and duplications are associated with variable phenotypes including autism, head circumference and height defects. To elucidate which gene(s) are responsible for the 1q21.1 duplication/deletion-associated phenotypes, we performed gene manipulation in zebrafish and mice. We modeled 1q21.1 duplication by overexpressing the eight human protein-coding genes in zebrafish. We found that only overexpression of CHD1L led to macrocephaly and increased larval body length, whereas chd1l deletion caused opposite phenotypes. These mirrored phenotypes were also observed in mouse embryos. Transcriptomic, cistromic, and chromatin accessibility analyses of CHD1L knock-out hiPSC-derived neuronal progenitor cells revealed that CHD1L regulates the expression levels and chromatin accessibility of genes involved in neuronal differentiation and synaptogenesis, including autism genes. Moreover, we found that CHD1L favors telencephalon development during forebrain regionalization by facilitating chromatin accessibility to pioneer transcription factors, including SOX2 and OTX2, while simultaneously compacting chromatin through its interaction with the repressor NuRD complex. Overall, our data reveal a novel role for CHD1L as a master regulator of cell fate and its dosage imbalance contributes to the neuroanatomical and growth phenotypes associated with the 1q21.1 distal CNV.
Chromosome segments can sometimes be lost or duplicated. One such region called 1q21.1 on chromosome 1 is linked to autism and differences in head size and growth. In zebrafish and mice, we found that CHD1L, located in the 1q21.1 region, affects these traits. Its overexpression caused larger heads and bodies, while loss of the gene caused smaller growth. In human neuronal progenitors and cerebral organoids, CHD1L was found to control genes important for brain development, cell fate decision and neuronal connectivity by altering how DNA is packed and accessed. This regulation helps guide early brain formation. Imbalanced levels of CHD1L may therefore explain the developmental and growth differences seen in individuals with 1q21.1 duplication or deletion.
© The Author(s) 2025. Published by Oxford University Press.