Systematic discovery of regulatory motifs in conserved regions of the human genome, including thousands of CTCF insulator sites
- 24 April 2007
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 104 (17), 7145-7150
- https://doi.org/10.1073/pnas.0701811104
Abstract
Conserved noncoding elements (CNEs) constitute the majority of sequences under purifying selection in the human genome, yet their function remains largely unknown. Experimental evidence suggests that many of these elements play regulatory roles, but little is known about regulatory motifs contained within them. Here we describe a systematic approach to discover and characterize regulatory motifs within mammalian CNEs by searching for long motifs (12–22 nt) with significant enrichment in CNEs and studying their biochemical and genomic properties. Our analysis identifies 233 long motifs (LMs), matching a total of ≈60,000 conserved instances across the human genome. These motifs include 16 previously known regulatory elements, such as the histone 3′-UTR motif and the neuron-restrictive silencer element, as well as striking examples of novel functional elements. The most highly enriched motif (LM1) corresponds to the X-box motif known from yeast and nematode. We show that it is bound by the RFX1 protein and identify thousands of conserved motif instances, suggesting a broad role for the RFX family in gene regulation. A second group of motifs (LM2*) does not match any previously known motif. We demonstrate by biochemical and computational methods that it defines a binding site for the CTCF protein, which is involved in insulator function to limit the spread of gene activation. We identify nearly 15,000 conserved sites that likely serve as insulators, and we show that nearby genes separated by predicted CTCF sites show markedly reduced correlation in gene expression. These sites may thus partition the human genome into domains of expression.This publication has 29 references indexed in Scilit:
- In vivo enhancer analysis of human conserved non-coding sequencesNature, 2006
- Comparative genomics modeling of the NRSF/REST repressor network: From single conserved sites to genome-wide repertoireGenome Research, 2006
- Insulators: exploiting transcriptional and epigenetic mechanismsNature Reviews Genetics, 2006
- Systematic Analysis of Head-to-Head Gene Organization: Evolutionary Conservation and Potential Biological RelevancePLoS Computational Biology, 2006
- A distal enhancer and an ultraconserved exon are derived from a novel retroposonNature, 2006
- Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomesGenome Research, 2005
- Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammalsNature, 2005
- Conserved non-genic sequences — an unexpected feature of mammalian genomesNature Reviews Genetics, 2005
- Highly Conserved Non-Coding Sequences Are Associated with Vertebrate DevelopmentPLoS Biology, 2004
- A gene atlas of the mouse and human protein-encoding transcriptomesProceedings of the National Academy of Sciences of the United States of America, 2004