Single-Cell Atlas of Transcription and Chromatin States Reveals Regulatory Programs in the Human Brain

Xie, Y.; Chang, L.; Zhong, G.; Rink, J. A.; Baez-Becerra, T.; Armand, E.; Ding, W.; Li, K.; Boone, E.; Lie, A.; Indralingam, H. S.; Dong, K.; Loe, T.; Huang, B.; Wang, Z.; Barcoma, A. S.; Willier, J. K.; Knutson, K. W.; Liu, J.; Cho, S.; Cao, S.; Russo, K. G.; Young, C. K.; Arzavala, J.; Sanchez, Y.; Bikkina, A.; Schenker-Ahmed, N.; Kern, C.; Zhao, Z.; Klein, A.; Flores, J.; Tai, C.-Y.; Olness, J.; Monell, A.; Moghadami, S.; Barragan, C.; Chen, C.; Owens, W.; OConnor, C.; Liem, M.; Marrin, M. V.; Rose, C.; Alt, S. N.; Emerson, N.; Osteen, J.; Lucero, J.; Li, D.; Hodge, R. D.; Wang, T.; Keene,

doi:10.64898/2026.02.02.703166

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bioRxiv · 10.64898/2026.02.02.703166

Single-Cell Atlas of Transcription and Chromatin States Reveals Regulatory Programs in the Human Brain

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Abstract

Directly measuring chromatin states alongside transcription is essential for understanding how cell-type-specific regulatory programs are established and maintained in the adult human brain. We present a large-scale single-cell multimodal atlas generated by jointly profiling transcriptome with active (H3K27ac) and repressive (H3K27me3) histone modifications across 18 brain regions. We profile >750,000 nuclei spanning 160 cell types and integrate these data with chromatin accessibility, DNA methylation, 3D genome architecture, and spatial transcriptome. This framework annotates >500,000 regulatory elements and resolves cell-type-specific chromatin states. We link enhancers to target genes, infer gene regulatory networks, and classify chromatin interactions, revealing neuron-enriched long-range Polycomb repression of developmental genes. Integrating these maps with GWAS data and sequence-based model prioritizes noncoding variants, effector genes, and vulnerable cell types for neuropsychiatric disorders. Finally, cross-species comparisons show conserved activation but more divergent repression. Together, this study provides a functional reference for interpreting noncoding variants, epigenetic memory, and brain organization. HIGHLIGHTSO_LIJoint single-cell profiling of transcriptomes with active or repressive histone modification in >750,000 nuclei across adult human brain. C_LIO_LIChromatin state annotation of >500,000 candidate cis-regulatory elements distinguishes active enhancers from accessible and Polycomb-repressed regions. C_LIO_LICell-type-resolved regulatory networks and sequence-based deep learning model prioritize functional neuropsychiatric risk variants. C_LIO_LISpatial epigenomic imputation reveals laminar layer-specific Polycomb repression programs. C_LIO_LIIntegration with 3D genome architecture reveals neuron-specific super long-range chromatin loops silencing early developmental genes. C_LIO_LIEvolutionary analysis uncovers conserved active regulatory grammar but divergent repressive landscape. C_LI

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Xie, Y., Chang, L., Zhong, G., Rink, J. A., Baez-Becerra, T., Armand, E., Ding, W., Li, K., Boone, E., Lie, A., Indralingam, H. S., Dong, K., Loe, T., Huang, B., Wang, Z., Barcoma, A. S., Willier, J. K., Knutson, K. W., Liu, J., Cho, S., Cao, S., Russo, K. G., Young, C. K., Arzavala, J., Sanchez, Y., Bikkina, A., Schenker-Ahmed, N., Kern, C., Zhao, Z., Klein, A., Flores, J., Tai, C.-Y., Olness, J., Monell, A., Moghadami, S., Barragan, C., Chen, C., Owens, W., OConnor, C., Liem, M., Marrin, M. V., Rose, C., Alt, S. N., Emerson, N., Osteen, J., Lucero, J., Li, D., Hodge, R. D., Wang, T., Keene,. 2026-02-03. Single-Cell Atlas of Transcription and Chromatin States Reveals Regulatory Programs in the Human Brain. https://doi.org/10.64898/2026.02.02.703166

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