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Enhancer Features that Drive Formation of Transcriptional Condensates.

Krishna Shrinivas1, Benjamin R Sabari2, Eliot L Coffey3

  • 1Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

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Summary

DNA sequence features like TF binding site number and density drive the formation of transcriptional condensates. These DNA-driven condensates enhance gene transcription, revealing a new genome-scaffolding mechanism for gene regulation.

Keywords:
coactivatorcondensatecooperativityenhancermultivalencephase separationregulatory elementspecificitytranscriptiontranscription factor

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Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Enhancers are DNA elements crucial for gene regulation, binding transcription factors (TFs) to recruit transcriptional machinery.
  • Phase-separated condensates of TFs and coactivators are known to assemble transcription machinery at enhancers.
  • The specific role of DNA sequence in driving these phase separation events at enhancers remained unexplored.

Purpose of the Study:

  • To investigate how DNA sequences influence the formation of transcription factor and coactivator condensates at enhancers.
  • To determine if specific DNA sequence features can drive phase separation and regulate enhancer activity.

Main Methods:

  • Investigated the impact of transcription factor binding site number, density, and affinity on condensate formation.
  • Utilized a combination of structured TF-DNA interactions and multivalent TF-coactivator interactions.
  • Assessed enhancer activity and transcription in cellular models.

Main Results:

  • Specific thresholds in TF binding site number, density, and affinity within DNA sequences were found to drive TF and coactivator condensation.
  • Condensate formation at specific genomic loci is determined by the DNA sequence and the available TFs.
  • DNA features that promote condensation also enhance enhancer activity and gene transcription.

Conclusions:

  • The genome's DNA sequence can actively scaffold transcriptional condensates at specific loci.
  • Phase separation, driven by DNA sequence properties, provides a mechanism for precise gene regulation.
  • This study offers a framework for understanding how DNA sequence dictates the spatial organization of transcription.