Toward decoding the mechanisms that shape sub-megabase-scale genome organization

Understanding genome organization at the kilobase to megabase scale is critical, as it encompasses genes and regulatory elements. Improvements in the resolution of experimental techniques have revealed novel structural motifs at this scale, including micro-compartments, nucleosome clutches, microdomains, and packing domains. Here we review recent progress on developing theories to explain these observations. Key advances include elucidating the role of nucleosome positioning and epigenetic modifications, the role and mechanisms of compartmentalization in local structure, and the interplay between loop extrusion and phase separation. This work has revealed probable mechanisms by which the observed structures emerge, but it remains unclear how these factors act together in the cell. To this end, recent studies have used chromatin conformation capture data in concert with diverse genomics datasets to create native-like models of chromatin at nucleosome resolution and below. While several roadblocks remain, this strategy promises to decode how molecular forces sum to shape chromatin structure and ultimately regulate transcription.