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

Joan M Pulupa1,2, Natalie G McArthur3, Olga Stathi2

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DNA sequence variations drive the formation of stable, long-range genomic contacts. These interactions, crucial for cellular identity, occur via transcription factor (TF) driven nucleoprotein condensates.

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Area of Science:

  • Molecular Biology
  • Genomics
  • Cell Biology

Background:

  • Ultra long-range genomic contacts are key to genome architecture but pose a biochemical paradox.
  • Regulatory DNA elements selectively contact distant sequences over proximal ones, even with identical transcription factors (TFs).

Purpose of the Study:

  • To investigate the mechanism behind the stability and specificity of long-range genomic contacts.
  • To understand how transcription factor binding leads to selective, multi-chromosomal enhancer hub formation.

Main Methods:

  • In vitro reconstitution of enhancer hubs.
  • Analysis of transcription factor motif variations.
  • Live imaging and single-molecule tracking of proteins in cultured olfactory sensory neurons (OSNs).

Main Results:

  • Transcription factor motif variations induce distinct homotypic properties in Lhx2/Ebf1/Ldb1 complexes.
  • These properties enable the formation of nucleoprotein condensates with solid-phase characteristics.
  • In vivo studies confirm the assembly of transcription-competent solid condensates at physiological protein concentrations.

Conclusions:

  • DNA sequence-induced homophilic nucleoprotein interactions explain the stability and specificity of long-range genomic contacts.
  • This mechanism provides a generalizable model for controlling cellular identity and function through genome architecture.