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HOX Loci Focused CRISPR/sgRNA Library Screening Identifying Critical CTCF Boundaries
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Published on: March 31, 2019

E2-mediated cathepsin D (CTSD) activation involves looping of distal enhancer elements.

Nancy Bretschneider1, Sara Kangaspeska, Martin Seifert

  • 1European Molecular Biology Laboratory, Meyerhofstrasse 1, D-69117 Heidelberg, Germany. bretschn@embl.de

Molecular Oncology
|April 23, 2009
PubMed
Summary

Estrogen receptor alpha (ERalpha) regulates cathepsin D (CTSD) expression via a distal enhancer. This study reveals ERalpha

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Dissection of Enhancer Function Using Multiplex CRISPR-based Enhancer Interference in Cell Lines

Published on: June 2, 2018

Area of Science:

  • Molecular Biology
  • Epigenetics
  • Gene Regulation

Background:

  • Estrogen receptor alpha (ERalpha) is a transcription factor regulating gene expression through estrogen response elements (EREs).
  • ERalpha binding sites are often found outside proximal promoter regions, suggesting distal regulatory mechanisms.
  • The cathepsin D gene (CTSD) is a known estrogen-responsive gene, but its distal regulation is not fully understood.

Purpose of the Study:

  • To characterize a distal estrogen response element (ERE) upstream of the cathepsin D (CTSD) gene.
  • To investigate the role of ERalpha and DNA methylation in regulating CTSD expression through distal elements.
  • To elucidate the mechanism of long-distance gene regulation involving ERalpha and CTSD.

Main Methods:

  • Chromatin immunoprecipitation (ChIP) to detect ERalpha and phosphorylated RNA Polymerase II (PolII) binding.
  • Analysis of transient CpG methylation kinetics at the CTSD promoter and distal enhancer.
  • Functional assays in MCF-7 cells to assess CTSD expression regulation.

Main Results:

  • An ERE located 9kbp upstream of the CTSD transcription start site (TSS) was identified and characterized.
  • Estrogen stimulation up-regulates CTSD expression via this distal ERE in MCF-7 cells.
  • ERalpha and phosphorylated PolII are recruited to the CTSD distal enhancer upon estrogen stimulation.
  • Transient CpG methylation occurs at both the CTSD promoter and the distal enhancer.
  • ERalpha mediates long-distance regulation of CTSD expression through a DNA looping mechanism.

Conclusions:

  • Estrogen receptor alpha (ERalpha) controls cathepsin D (CTSD) expression via a distal enhancer element through a DNA looping mechanism.
  • This distal regulation involves the recruitment of ERalpha and PolII and is associated with transient DNA methylation changes.
  • The findings highlight the importance of distal regulatory elements in ERalpha-mediated gene expression and epigenetic modifications.