The genomic DNA of a human cell is approximately 2-m long when straightened but is highly folded in a nucleus that is typically 5–10 µm in diameter [6]. Through the use of microscopic and high-throughput chromosome conformation capture (Hi-C) techniques, it has been revealed that chromatin forms a fractal globule with compartments, chromatin domains, and loop interactions [7]. At the megabase scale, chromatin is divided into two spatially segregated compartments, arbitrarily labeled as A and B, with different transcriptional activity [8]. The euchromatic A compartment adopts a central position, whereas the heterochromatic B compartment locates toward the nuclear periphery and perinucleolar regions [9]. This nuclear organization appears to be conserved from ciliate to human during evolution [10]. The A and B compartments are closely linked to functional partitions of the genome, including histone modifications, gene expression, and DNA replication timing, as well as primary sequence features such as gene density and CpG frequency 11, 12, 13••, 14, 15, 16. Although euchromatin and heterochromatin has been known for 100 years [1], the molecular basis and the mechanism responsible for the segregation of active and inactive compartments remain elusive. The field has primarily focused on studying chromatin architectural proteins and cataloging cellular transcriptional and epigenetic maps 7, 15, 16, 17. Two recent studies by Lu et al. take an entirely new perspective by considering that structural information might be embedded in the genome itself 4••, 5••. In this article, we summarize and discuss the key findings related to the conservation and dynamics of gene regulation.