Lamins organize the three dimensional genome from nuclear periphery in ES cells

Lamins are the major structural components of the nuclear lamina (NL) beneath the inner nuclear membrane. Although lamins are believed to regulate genome organization and transcription, how they perform these functions remains poorly understood. Combining Hi-C with fluorescence in situ hybridization (FISH) and Histone and Lamina landscape (HiLands) analyses of chromatin domains, we show that lamins differentially regulate the NL-associated HiLands-P and -B domains in mouse ES cells (mESCs). Lamin loss leads to HiLands-P expansion at the NL, detachment of HiLands-B from the NL, and genome-wide changes of 3D chromatin interactions in NL-associated and interior HiLands in mESCs. Further epigenome and transcriptome analyses show that lamins can function from the NL to maintain the boundaries of active and repressive chromatin domains, thereby influencing gene expression throughout the genome. These findings should provide the basis to further understand how changes in the NL-associated chromatin influence transcription in development and NL-associated diseases. Overall design: Comparison of transcriptome (RNA-seq, 2 replicates), histone modifications(H3K4me3, H3K27me3, H3K9me3, H3K4me1, H3K27Ac, each 3-4 replicates), and 3D genome organization (Hi-C, 2 replicates) in WT and lamin-B1/B2/A triple knockout mESCs.