Orphan CpG Islands Amplify Poised Enhancer Regulatory Activity and Determine Target Gene Responsiveness

Overview

Journal Nat Genet

Specialty Genetics

Date 2021 Jun 29

PMID 34183853

Citations 49

Authors

Tomas Pachano

Victor Sanchez-Gaya

Thais Ealo

Maria Mariner-Fauli

Tore Bleckwehl

Helena G Asenjo

Patricia Respuela

Sara Cruz-Molina

Maria Munoz-San Martin

Endika Haro

Wilfred F J van IJcken

David Landeira

Alvaro Rada-Iglesias

Affiliations

Soon will be listed here.

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.

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