Genevieve, D. | bioRxiv Science

bioRxiv2025

Disrupted transcriptional networks regulated by CHD1L during neurodevelopment underlie the mirrored neuroanatomical and growth phenotypes of the 1q21.1 copy number variant

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 overexpression of CHD1L only 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. Last, atypical 1q21.1 CNV encompassing CHD1L and pathogenic missense and truncating CHD1L variants were found in individuals with autism. 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. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/638841v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@7dd5borg.highwire.dtl.DTLVardef@55a12dorg.highwire.dtl.DTLVardef@1c8ce0corg.highwire.dtl.DTLVardef@4faf29_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Chromatin condensates tune nuclear mechano-sensing in Kabuki Syndrome by constraining cGAS activation

Cells and tissue integrity is constantly challenged by the necessity to adapt and respond to mechanical loads. Among the cellular components, the nucleus possesses mechano-sensing and mechanotransduction capabilities, yet the molecular mechanisms involved remain poorly defined. We postulated that the mechanical properties of the chromatin and its compartmentalization into condensates contribute to the nuclear adaptation to external forces, while preserving its integrity. By interrogating the effects of MLL4 loss-of-function in Kabuki Syndrome, we found that the balancing of transcriptional and Polycomb condensates tunes the nuclear responsiveness to external mechanical forces. We showed that MLL4 acts as a chromatin mechano-sensor by clustering into condensates through its Prion-like domain, and its response was regulated by the chromatin context. Furthermore, the mechano-sensing activity of MLL4 condensates is instrumental to withstand the physical challenges that nuclei experience during cell confinement and migration by preserving their integrity. In Kabuki Syndrome persistent rupture of nuclear envelope triggers cGAS-STING activation, which leads to programmed cell death. Ultimately, these results demonstrate the critical role chromatin compartments play in mechano-responses and how they impact pathological conditions by stimulating cGAS-STING signaling.

molecular biology↗