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Extensive enhancer crosstalk controls PPARG2 activation during adipogenesis.

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Master regulators like peroxisome proliferator-activated receptor gamma (PPARγ) control cell fate. This study reveals enhancer crosstalk crucial for PPARγ activation during fat cell differentiation, impacting cardiometabolic health.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Cell fate transitions are governed by transcriptional master regulators.
  • Peroxisome proliferator-activated receptor gamma (PPARγ) is essential for adipogenesis (fat cell formation).
  • Tight regulation of PPARγ expression is critical for adipocyte differentiation.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of the enhancer network controlling PPARG gene activation.
  • To investigate enhancer crosstalk in cis during human mesenchymal stem cell adipogenesis.
  • To understand the role of specific enhancers in PPARγ expression and cardiometabolic traits.

Main Methods:

  • Systematic deletion of nine enhancers within the PPARG locus.
  • Analysis of enhancer-promoter interactions and chromatin remodeling.
  • Assessment of transcription factor binding, including C/EBPβ.
  • Mapping of non-coding genetic variants to regulatory elements.

Main Results:

  • Demonstrated intricate enhancer crosstalk in cis, stabilizing C/EBPβ binding before chromatin remodeling.
  • Identified enhancer E+102 as critical for cis crosstalk, feedback activation, and PPARG expression.
  • Showed that genetic variants linked to cardiometabolic diseases reside in key enhancers, including E+102.

Conclusions:

  • Enhancer communities and their crosstalk are vital for regulating master regulators like PPARγ.
  • The identified regulatory mechanisms of PPARG are crucial for adipogenesis and human physiology.
  • Dysregulation of these enhancers may contribute to cardiometabolic diseases.