PuSH - Publication Server of Helmholtz Zentrum München: Joint epigenome profiling reveals cell-type-specific gene regulatory programmes in human cortical organoids.

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Noack, F. ; Vangelisti, S. ; Ditzer, N.* ; Chong, F. ; Albert, M.* ; Bonev, B.

Joint epigenome profiling reveals cell-type-specific gene regulatory programmes in human cortical organoids.

Nat. Cell Biol. 12, 1873-1883 (2023)

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Gene expression is regulated by multiple epigenetic mechanisms, which are coordinated in development and disease. However, current multiomics methods are frequently limited to one or two modalities at a time, making it challenging to obtain a comprehensive gene regulatory signature. Here, we describe a method—3D genome, RNA, accessibility and methylation sequencing (3DRAM-seq)—that simultaneously interrogates spatial genome organization, chromatin accessibility and DNA methylation genome-wide and at high resolution. We combine 3DRAM-seq with immunoFACS and RNA sequencing in cortical organoids to map the cell-type-specific regulatory landscape of human neural development across multiple epigenetic layers. Finally, we apply a massively parallel reporter assay to profile cell-type-specific enhancer activity in organoids and to functionally assess the role of key transcription factors for human enhancer activation and function. More broadly, 3DRAM-seq can be used to profile the multimodal epigenetic landscape in rare cell types and different tissues.

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