POGZ safeguards neuronal gene chromatin architecture and transcription

Mariano, N. A.; Williams, K. J.; Munechika, K.; Bonefas, K. M.; Sun, Y.; Zhang, W.; Klein, J. L.; Monahan, K.; Yu, H.; Feschotte, C.; Markenscoff, E.

doi:10.64898/2026.07.02.736104

bioRxiv · 10.64898/2026.07.02.736104

POGZ safeguards neuronal gene chromatin architecture and transcription

Mariano, N. A.·Williams, K. J.·Munechika, K.·Bonefas, K. M.·Sun, Y.·Zhang, W.·Klein, J. L.·Monahan, K.·Yu, H.·Feschotte, C.·Markenscoff, E.

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Abstract

Disruption of chromatin organization is a common pathogenic mechanism in neurodevelopmental disorders, yet how changes in 3D genome architecture relate to transcriptional dysfunction in the developing brain remains unclear. POGZ, a transposase-derived chromatin regulator mutated in White-Sutton syndrome and autism spectrum disorder (ASD) has been linked to both heterochromatin and accessible regulatory DNA, but its in vivo function in the brain is unresolved. Using immunoprecipitation-mass spectrometry in embryonic day 13.5 (E13.5) mouse cortex, we identify the H3K9 methyltransferases G9a/GLP as principal POGZ interactors, placing POGZ within the core H3K9 methylation machinery in vivo. We find that POGZ loss in embryonic mouse cortex drives bidirectional, megabase-scale redistribution of H3K9me3, with ectopic losses and gains over discrete neuronal gene loci. In developing Pogz-/-cortex, regions with H3K9me3 gains are repositioned to the nuclear lamina and exhibit strengthened B-compartment scores by Micro-C, locus-restricted erosion of TAD architecture, weakened boundary insulation, and reduced CTCF occupancy. Within these domains, nascent RNA synthesis at neuronal genes is markedly diminished. These results identify POGZ as a G9a/GLP-associated chromatin regulator that protects neurodevelopmental gene domains from heterochromatinization and perinuclear sequestering, preserving 3D architecture and transcription during cortical development. Major PointsO_LIPOGZ interacts with the G9a/GLP H3K9 methyltransferase complex in the developing mouse cortex, identified by IP-mass spectrometry. C_LIO_LILoss of POGZ drives megabase-scale redistribution of H3K9me3 and increases compartmentalization and nuclear-lamina association of neurodevelopmental gene loci, shown by ChIP-seq, Micro-C, and DNA FISH. C_LIO_LIMicro-C reveals disrupted TAD architecture at specific neuronal gene loci in Pogz-/-.PRO-seq shows POGZ is required to maintain nascent RNA synthesis of neurodevelopmental genes within disrupted chromatin domains. C_LI

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Mariano, N. A., Williams, K. J., Munechika, K., Bonefas, K. M., Sun, Y., Zhang, W., Klein, J. L., Monahan, K., Yu, H., Feschotte, C., Markenscoff, E.. 2026-07-03. POGZ safeguards neuronal gene chromatin architecture and transcription. https://doi.org/10.64898/2026.07.02.736104

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