Widespread Alu repeat-driven expansion of consensus DR2 retinoic acid response elements during primate evolution

Area of Science:

• Genomics
• Evolutionary Biology
• Molecular Biology

Background:

• Nuclear receptors are crucial transcription factors regulating development and physiology.
• Hormone response elements (HREs), like DR1-DR5, are key DNA motifs recognized by nuclear receptors.
• The evolutionary divergence of nuclear receptor regulation in primates remains largely unexplored.

Purpose of the Study:

• To map all DR-type HREs in the human genome.
• To investigate the role of Alu repeats in the evolution of nuclear receptor binding sites.
• To understand the specific contribution of Alu-mediated expansion to primate and human gene regulation.

Main Methods:

• Genome-wide mapping of DR-type HREs.
• Bioinformatic analysis of HRE distribution within repetitive elements, particularly Alu sequences.
• Chromatin immunoprecipitation (ChIP) and ChIP-on-chip assays to detect in vivo receptor binding.

Main Results:

• DR2 motifs, recognized by retinoic acid receptors (RARs), are highly abundant in the human genome (108,582 elements).
• Approximately 90% of DR2 motifs are located within Alu repeats, with 50% of DR4 motifs also found in Alu elements.
• Alu-mediated expansion, driven by deamination of CpG dinucleotides, generated numerous Alu-DR2 elements adjacent to RAR target genes, confirmed by in vivo RAR binding via ChIP assays.

Conclusions:

• Alu repeats have significantly contributed to the expansion and evolution of DR elements in primates.
• Alu-mediated expansion of DR elements played a critical role in the evolution of gene regulation by RARs and other nuclear receptors in humans.
• This study provides strong evidence for the impact of repetitive elements on the regulatory landscape of primate genomes.