1. Academic Validation
  2. Spatial 3D genome organization controls the activity of bivalent chromatin during human neurogenesis

Spatial 3D genome organization controls the activity of bivalent chromatin during human neurogenesis

  • bioRxiv. 2024 Aug 1:2024.08.01.606248. doi: 10.1101/2024.08.01.606248.
Sajad Hamid Ahanger 1 2 Chujing Zhang 1 2 Evan R Semenza 1 2 Eugene Gil 1 2 Mitchel A Cole 1 2 Li Wang 3 2 Arnold R Kriegstein 3 2 Daniel A Lim 1 2 4
Affiliations

Affiliations

  • 1 Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 2 Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 3 Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 4 San Francisco Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Abstract

The nuclear genome is spatially organized into a three-dimensional (3D) architecture by physical association of large chromosomal domains with subnuclear compartments including the nuclear lamina at the radial periphery and nuclear speckles within the nucleoplasm1-5. However, how spatial genome architecture regulates human brain development has been overlooked owing to technical limitations. Here, we generate high-resolution maps of genomic interactions with the lamina and speckles in cells of the neurogenic lineage isolated from midgestational human cortex, uncovering an intimate association between subnuclear genome compartmentalization, chromatin state and transcription. During cortical neurogenesis, spatial genome organization is extensively remodeled, relocating hundreds of neuronal genes from the lamina to speckles including key neurodevelopmental genes bivalent for H3K27me3 and H3K4me3. At the lamina, bivalent genes have exceptionally low expression, and relocation to speckles enhances resolution of bivalent chromatin to H3K4me3 and increases transcription >7-fold. We further demonstrate that proximity to the nuclear periphery - not the presence of H3K27me3 - is the dominant factor in maintaining the lowly expressed, poised state of bivalent genes embedded in the lamina. In addition to uncovering a critical role of subnuclear genome compartmentalization in neurogenic transcriptional regulation, our results establish a new paradigm in which knowing the spatial location of a gene is necessary to understanding its epigenomic regulation.

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