  Current models for the folding of the human genome see a hierarchy stretching
down from chromosome territories, through A/B compartments and TADs
(topologically-associating domains), to contact domains stabilized by cohesin
and CTCF. However, molecular mechanisms underlying this folding, and the way
folding affects transcriptional activity, remain obscure. Here we review
physical principles driving proteins bound to long polymers into clusters
surrounded by loops, and present a parsimonious yet comprehensive model for the
way the organization determines function. We argue that clusters of active RNA
polymerases and their transcription factors are major architectural features;
then, contact domains, TADs, and compartments just reflect one or more loops
and clusters. We suggest tethering a gene close to a cluster containing
appropriate factors -- a transcription factory -- increases the firing
frequency, and offer solutions to many current puzzles concerning the actions
of enhancers, super-enhancers, boundaries, and eQTLs (expression quantitative
trait loci). As a result, the activity of any gene is directly influenced by
the activity of other transcription units around it in 3D space, and this is
supported by Brownian-dynamics simulations of transcription factors binding to
cognate sites on long polymers.
