Orphan CpG islands amplify poised enhancer regulatory activity and determine target gene responsiveness

Tomas Pachano1,2, Víctor Sánchez-Gaya2, Thais Ealo2, Maria Mariner-Faulí2, Tore Bleckwehl1, Helena G Asenjo3,4,5, Patricia Respuela2, Sara Cruz-Molina6, María Muñoz-San Martín2, Endika Haro2, Wilfred F J van IJcken7, David Landeira3,4,5, Alvaro Rada-Iglesias8,9,10

  1. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
  2. Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/Universidad de Cantabria/SODERCAN, Santander, Spain.
  3. Centre for Genomics and Oncological Research (GENYO), Granada, Spain.
  4. Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain.
  5. Instituto de Investigación Biosanitaria ibs.GRANADA, Hospital Virgen de las Nieves, Granada, Spain.
  6. Max Planck Institute for Molecular Biomedicine, Muenster, Germany.
  7. Center for Biomics, Erasmus University Medical Center, Rotterdam, the Netherlands.
  8. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. alvaro.rada@unican.es.
  9. Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), CSIC/Universidad de Cantabria/SODERCAN, Santander, Spain. alvaro.rada@unican.es.
  10. Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. alvaro.rada@unican.es.

Abstract

CpG islands (CGIs) represent a widespread feature of vertebrate genomes, being associated with ~70% of all gene promoters. CGIs control transcription initiation by conferring nearby promoters with unique chromatin properties. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance is barely known. Here we show that oCGIs are an essential component of poised enhancers that augment their long-range regulatory activity and control the responsiveness of their target genes. Using a knock-in strategy in mouse embryonic stem cells, we introduced poised enhancers with or without oCGIs within topologically associating domains harboring genes with different types of promoters. Analysis of the resulting cell lines revealed that oCGIs act as tethering elements that promote the physical and functional communication between poised enhancers and distally located genes, particularly those with large CGI clusters in their promoters. Therefore, by acting as genetic determinants of gene-enhancer compatibility, CGIs can contribute to gene expression control under both physiological and potentially pathological conditions.

Presented By Tomas Pachano | ORCID iD

Genetics & Genome BiologyNicholas Liao2021-07 (Jul)