De novo DNA demethylation and noncoding transcription define active intergenic regulatory elements

Area of Science:

• Genomics and Epigenetics
• Developmental Biology
• Gene Regulation

Background:

• Deep sequencing revealed numerous intergenic hypomethylated regions (iHMRs) in mammalian DNA.
• The functional significance and dynamic establishment of these iHMRs during development were previously unclear.

Purpose of the Study:

• To define functional classes of iHMRs using multi-omics data.
• To reconstruct the dynamic establishment of iHMRs during mammalian development.
• To investigate the role of transcription and sequence features in iHMR formation and maintenance.

Main Methods:

• Combined whole-genome bisulfite sequencing with gene expression and chromatin-state data.
• Comparative analysis of HMR profiles in embryonic stem cells and primary blood cells.
• Analysis of sequence conservation and variation across species and populations.

Main Results:

• iHMRs mark a subset of active DNase hypersensitive sites (DHS), exhibiting chromatin states of regulatory elements.
• Changes in iHMRs are more predictive of nearby gene activity than promoter methylation.
• Conserved sequence features, including TATA motifs, suggest a role for transcription in iHMRs, particularly in active enhancers.

Conclusions:

• A three-step model for iHMR establishment during development was proposed, involving pre-establishment in stem cells, partial demethylation in progenitors, and full formation with transcription during enhancer activation.
• Sequence plasticity and transcriptional signals significantly impact iHMR establishment and maintenance.
• iHMRs represent a conserved regulatory mechanism with functional implications for gene expression and cell differentiation.