DNA sequence-induced solid phase transition as a solution to the genome folding paradox

Ultra long-range genomic contacts, which emerge as prominent components of genome architecture, constitute a biochemical paradox. This is because regulatory DNA elements make selective and stable contacts with DNA sequences located megabases away, instead of interacting with proximal sequences occupied by the same exact transcription factors (TF). This is exemplified in olfactory sensory neurons (OSNs), where only a fraction of Lhx2/Ebf1/Ldb1-bound sites interact with each other, converging into highly selective multi-chromosomal enhancer hubs. In vitro hub reconstitution reveals that TF motif variations impose distinct homotypic properties to their resident Lhx2/Ebf1/Ldb1 complexes, enabling formation of nucleoprotein condensates with solid phase characteristics. Live imaging and single molecule tracking of Lhx2/Ebf1 proteins in cultured OSNs confirm that assembly of transcription-competent solid condensates occurs in vivo under physiological protein concentrations. Thus, DNA sequence-induced homophilic nucleoprotein interactions provide a generalizable explanation for the stability and specificity of long-range genomic contacts that control cellular identity and function.