Enhancer-silencer transitions in the human genome

Area of Science:

• Genomics
• Molecular Biology
• Developmental Biology

Background:

• Dual-function regulatory elements (REs) act as enhancers or silencers depending on cellular context.
• While studied in Drosophila, dual-function REs in mammals remain under-investigated.
• Understanding these elements is key to deciphering complex gene regulation.

Purpose of the Study:

• To systematically investigate dual-function REs in the human genome.
• To profile their activity across diverse cell types, focusing on T cell development.
• To identify REs with enhancer-silencer transition capabilities.

Main Methods:

• Developed a deep learning classifier to accurately identify REs.
• Profiled RE activity across multiple human cell types, including T cells and embryonic stem cells.
• Analyzed evolutionary patterns and mutation enrichment in identified dual-function REs.

Main Results:

• Identified approximately 12,000 silencers in T cells that function as enhancers in embryonic stem cells.
• These dual-function REs exhibit stronger purifying selection and are enriched for disease-associated mutations.
• Dual-function REs are frequently located near genes encoding transcriptional regulators (TFs) and chromatin remodelers.
• These elements contain distinct TF binding sites for activating or repressing functions.

Conclusions:

• Dual-function REs possess inherent functional plasticity, switching regulatory modes via differential TF recruitment.
• Over 6% of human cell type-specific silencers may be dual-function, representing a significant, overlooked regulatory class.
• The functional plasticity of these REs may contribute to human disease development.