Disruption of lamina-associated genome organization activates neuronal gene programs in H3.3K27M DIPG
- 1University of California, San Francisco
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor frequently driven by a histone H3 mutation that substitutes lysine 27 with methionine (H3K27M). While H3K27M is known to cause a global depletion of the repressive histone mark H3K27me3, how this epigenetic disruption contributes to oncogenic transcriptional reprogramming remains incompletely understood. Here, we show that H3.3K27M DIPG cells exhibit widespread disruption of lamina-associated domain (LAD) organization across primary tumors and patient-derived cell lines. H3.3K27M was enriched at genomic regions that lost lamina association, which acquired increased H3K27ac and showed activation of neuronal and oncogenic gene programs. Notably, LAD loss was more strongly associated with transcriptional activation than H3K27me3 depletion, linking altered LAD organization to the transcriptional consequences of H3.3K27M. Finally, expression of H3.3K27M in human embryonic stem cell-derived neural precursor cells (NPCs) was sufficient to induce LAD remodeling, predominantly through loss of lamina association, leading to activation of neuronal gene programs. Together, these findings identify disruption of lamina-associated genome architecture as a key mechanism by which the H3.3K27M oncohistone drives oncogenic transcriptional reprogramming in DIPG.
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BibTeX
@misc{ahanger2026disruption,
title = {{Disruption of lamina-associated genome organization activates neuronal gene programs in H3.3K27M DIPG}},
author = {S. H. Ahanger and M. A. Cole and E. Gil and E. R. Semenza and J. J. Phillips and D. A. Lim},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753114},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753114v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Disruption of lamina-associated genome organization activates neuronal gene programs in H3.3K27M DIPG
AU - S. H. Ahanger
AU - M. A. Cole
AU - E. Gil
AU - E. R. Semenza
AU - J. J. Phillips
AU - D. A. Lim
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753114
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753114v1
AB - Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor frequently driven by a histone H3 mutation that substitutes lysine 27 with methionine (H3K27M). While H3K27M is known to cause a global depletion of the repressive histone mark H3K27me3, how this epigenetic disruption contributes to oncogenic transcriptional reprogramming remains incompletely understood. Here, we show that H3.3K27M DIPG cells exhibit widespread disruption of lamina-associated domain (LAD) organization across primary tumors and patient-derived cell lines. H3.3K27M was enriched at genomic regions that lost lamina association, which acquired increased H3K27ac and showed activation of neuronal and oncogenic gene programs. Notably, LAD loss was more strongly associated with transcriptional activation than H3K27me3 depletion, linking altered LAD organization to the transcriptional consequences of H3.3K27M. Finally, expression of H3.3K27M in human embryonic stem cell-derived neural precursor cells (NPCs) was sufficient to induce LAD remodeling, predominantly through loss of lamina association, leading to activation of neuronal gene programs. Together, these findings identify disruption of lamina-associated genome architecture as a key mechanism by which the H3.3K27M oncohistone drives oncogenic transcriptional reprogramming in DIPG.
ER -