The human genome consists of approximately three billion nucleotides distributed amongst twenty-two autosomes and one sex chromosome. Most of our genes are encoded within these 23 chromosomes. With few exceptions, human cells contain two genome copies that if joined would measure over two meters in length. Chromosomes are thus extensively folded in order to fit within the ultra small, micrometer-scale confines of the cell nucleus.

Our genomic DNA is first packaged with histone and non-histone proteins in the form of chromatin. This packaging shortens chromosome length at least sevenfold. Chromatin then folds different ways in the nucleus: from high to low resolution, chromatin fibers first engage into so-called “looping contacts” where distal genomic regions are physically close to each other (see Summary Figure)[1]. Looping interactions can create microenvironments and result in the formation of small chromatin domains or “subTADs”. These domains are specific to cell types, and vary mostly based on chromatin composition and whether genes are expressed. SubTADs can interact with one another within the larger “topologically associating domains” (TADs). These are more conserved between cell types and even across species at synthenic regions. TADs then interact with each other, forming “metaTADs” along chromosomes. MetaTAD formation broadly depends on chromatin composition and transcription activity. Large chromatin domains also tend to congregate as “compartments” in the nuclear space when they have similar composition and activity. Consequently to this extensive chromatin folding, chromosomes each occupy their own nuclear territory (CT), although chromatin from different chromosomes can also interact.