Spatial 3D genome organization controls the activity of bivalent chromatin during human neurogenesis [RNA-seq]
Subnuclear compartments including the nuclear lamina and speckles organize the genome in three-dimensional (3D) space and regulate gene expression. By studying the neurogenic cell lineage isolated directly from the human brain, we show that lamina association plays a dominant role in maintaining the lowly expressed, poised state of key developmental genes bivalent for H3K27me3 and H3K4me3. During neurogenesis, large regions of the genome relocate from the lamina to speckles, corresponding to enhanced resolution of bivalent chromatin to monovalent H3K4me3 and a ~7-fold increase in transcription. Using cell culture models of human neurogenesis, we confirm the bivalent state of lamina-associated genes and provide further evidence that lamina association contributes strongly to the low expression of bivalent genes independent of H3K27me3.  These data support a model in which spatial location of genomic regions in relation to subnuclear structures plays a dominant role in regulating the activity of chromatin state and lineage-specific gene expression. Overall design: RNA-seq of iPSC-derived NPCs and iPSC-derived neurons (iN); RNA-seq of ESC-derived NPCs treated with DMSO or EZH2 inhibitor, EPZ-6438