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Domain-Selective BET Ligands Yield Next-Generation Synthetic Genome Readers/Regulators with Nonidentical Cellular

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Synthetic genome regulators (SynGRs) targeting Friedreich's ataxia show that engaging BET bromodomain 2 (BD2) is key for FXN gene expression, while BD1 inhibition enhances SynGR activity.

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Area of Science:

  • Epigenetics and Gene Regulation
  • Synthetic Biology
  • Molecular Pharmacology

Background:

  • Friedreich's ataxia is a genetic disorder caused by reduced expression of the frataxin (FXN) gene, often due to GAA triplet repeat expansions.
  • Synthetic genome regulators (SynGRs) are engineered molecules designed to target specific DNA sequences and modulate gene expression.
  • Bromo- and extra-terminal domain (BET) proteins, particularly BRD4, play crucial roles in transcriptional regulation by recognizing acetylated lysine residues on histones via their bromodomains (BD1 and BD2).

Purpose of the Study:

  • To investigate the role of different BET bromodomains (BD1 and BD2) in the function of SynGRs designed to restore FXN expression.
  • To evaluate next-generation BET ligands as potential replacements for JQ1 in SynGR design for Friedreich's ataxia.
  • To elucidate the molecular mechanisms by which SynGRs engage BET proteins and regulate transcription.

Main Methods:

  • Design and synthesis of SynGRs incorporating sequence-selective DNA-binding polyamides and various BET ligands (pan-BET, BD1-selective, BD2-selective).
  • Testing the ability of SynGRs to recruit BRD4/BET proteins to GAA repeat loci in the FXN gene.
  • Assessing the transcriptional output at the FXN locus in the presence of different SynGR constructs and BET ligands, including co-treatment experiments.

Main Results:

  • SynGRs utilizing pan-BET or BD2-selective ligands successfully induced FXN transcription, while BD1-selective ligands failed to do so.
  • An untethered BD1-selective ligand (GSK778) unexpectedly enhanced the activity of all functional SynGRs when used in combination.
  • The findings suggest that active SynGRs function by mimicking natural transcription factors that engage BET proteins primarily through BD2 binding.

Conclusions:

  • Engaging BET bromodomain 2 (BD2) is essential for SynGR-mediated transcription of the FXN gene.
  • Blocking BET bromodomain 1 (BD1) with specific ligands enhances the efficacy of SynGRs, possibly by directing BET proteins to BD2.
  • SynGRs serve as valuable chemical probes for understanding gene regulation principles and designing improved synthetic gene regulators for therapeutic applications.