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Peer-reviewedCC BYNature

Subnuclear genome compartmentalization controls bivalent chromatin activity

  • Sajad Hamid Ahanger1,2
  • Evan R. Semenza3,1,2
  • Chujing Zhang1,2
  • Eugene Gil1,2
  • Mitchel A. Cole3,1,2,4
  • Serena Huei-An Lu3,1,2
  • Li Wang5,2
  • Arnold R. Kriegstein5,2
  • Daniel A. Lim6,7,8
8 affiliations
  1. 1Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA
  2. 2Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA
  3. 3Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA
  4. 4Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA, USA
  5. 5Department of Neurology, University of California, San Francisco, San Francisco, CA, USA
  6. 6Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. [email protected]
  7. 7Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. [email protected]
  8. 8San Francisco Veterans Affairs Health Care System, San Francisco, CA, USA. [email protected]
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Abstract

. However, how higher-order spatial genome architecture regulates human development has been overlooked, and the interplay between chromatin state and subnuclear genome compartmentalization is poorly understood. Here we generate high-resolution maps of genomic interactions with the lamina and speckles in cells of the neurogenic lineage isolated from mid-gestational human cortex, identifying an intimate association between subnuclear genome compartmentalization, chromatin state and transcription. During cortical neurogenesis, subnuclear genome compartmentalization is extensively remodelled, relocating hundreds of neuronal genes from the lamina to speckles, including key neurodevelopmental genes bivalent for trimethylation of histone H3 at Lys27 (H3K27me3) and Lys4 (H3K4me3). At the lamina, bivalent genes have exceptionally low expression, and relocation to speckles enhances resolution of bivalent chromatin to H3K4me3 monovalency and increases transcription more than eightfold. We further demonstrate that proximity to the nuclear periphery-not the presence of H3K27me3-maintains the lowly expressed, poised state of bivalent genes embedded in the lamina. We find that the repressive environment of the lamina is associated with spatial segregation of the transcriptional elongation machinery from the nuclear periphery. Our results establish a paradigm in which knowing the spatial location of a gene is necessary for understanding its epigenomic regulation.

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Cite

BibTeXRIS
BibTeX
@article{ahanger2026subnuclear,
  title = {{Subnuclear genome compartmentalization controls bivalent chromatin activity}},
  author = {Sajad Hamid Ahanger and Evan R. Semenza and Chujing Zhang and Eugene Gil and Mitchel A. Cole and Serena Huei-An Lu and Li Wang and Arnold R. Kriegstein and Daniel A. Lim},
  journal = {Nature},
  year = {2026},
  month = jul,
  doi = {10.1038/s41586-026-10832-w},
  url = {https://doi.org/10.1038/s41586-026-10832-w},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Subnuclear genome compartmentalization controls bivalent chromatin activity
AU  - Sajad Hamid Ahanger
AU  - Evan R. Semenza
AU  - Chujing Zhang
AU  - Eugene Gil
AU  - Mitchel A. Cole
AU  - Serena Huei-An Lu
AU  - Li Wang
AU  - Arnold R. Kriegstein
AU  - Daniel A. Lim
PY  - 2026
DA  - 2026/07/22
JO  - Nature
DO  - 10.1038/s41586-026-10832-w
UR  - https://doi.org/10.1038/s41586-026-10832-w
AB  - . However, how higher-order spatial genome architecture regulates human development has been overlooked, and the interplay between chromatin state and subnuclear genome compartmentalization is poorly understood. Here we generate high-resolution maps of genomic interactions with the lamina and speckles in cells of the neurogenic lineage isolated from mid-gestational human cortex, identifying an intimate association between subnuclear genome compartmentalization, chromatin state and transcription. During cortical neurogenesis, subnuclear genome compartmentalization is extensively remodelled, relocating hundreds of neuronal genes from the lamina to speckles, including key neurodevelopmental genes bivalent for trimethylation of histone H3 at Lys27 (H3K27me3) and Lys4 (H3K4me3). At the lamina, bivalent genes have exceptionally low expression, and relocation to speckles enhances resolution of bivalent chromatin to H3K4me3 monovalency and increases transcription more than eightfold. We further demonstrate that proximity to the nuclear periphery-not the presence of H3K27me3-maintains the lowly expressed, poised state of bivalent genes embedded in the lamina. We find that the repressive environment of the lamina is associated with spatial segregation of the transcriptional elongation machinery from the nuclear periphery. Our results establish a paradigm in which knowing the spatial location of a gene is necessary for understanding its epigenomic regulation.
SN  - 0028-0836
SN  - 1476-4687
ER  -