Genomes exist in vivo as complex physical structures, and their functional output (i.e. the gene expression profile of a cell) is related to their spatial organization inside the nucleus as well as to local chromatin status. Chromatin modifications and chromosome conformation are distinct in different tissues and cell types, which corresponds closely with the diversity in gene-expression patterns found in different tissues of the body. The biological processes and mechanisms driving these general correlations are currently the topic of intense study. An emerging theme is that genome compartmentalization - both along the linear length of chromosomes, and in three dimensions by the spatial colocalization of chromatin domains and genomic loci from across the genome - is a crucial parameter in regulating genome expression. In this Commentary, we propose that a full understanding of genome regulation requires integrating three different types of data: first, one-dimensional data regarding the state of local chromatin - such as patterns of protein binding along chromosomes; second, three-dimensional data that describe the population-averaged folding of chromatin inside cells and; third, single-cell observations of three-dimensional spatial colocalization of genetic loci and trans factors that reveal information about their dynamics and frequency of colocalization.