An Evolutionary Conserved Epigenetic Mark of Polycomb Response Elements Implemented by Trx/MLL/COMPASS

Area of Science:

• Epigenetics
• Developmental Biology
• Genomics

Background:

• Polycomb response elements (PREs) maintain gene expression patterns but their existence in mammals is debated.
• CpG islands are implicated in recruiting Polycomb group (PcG) complexes, yet specific PRE identification remains unclear.
• Trithorax (Trx) antagonizes PcG silencing by positively regulating gene expression.

Purpose of the Study:

• To investigate the role of Trithorax homologs in marking and maintaining mammalian Polycomb response elements (PREs).
• To elucidate the functional balance between MLL1 and Polycomb repressive complex 2 (PRC2) at CpG-dense regions.
• To establish criteria for identifying cell-type-specific functional mammalian PREs.

Main Methods:

• Utilized ChIP-seq to analyze H3K4me2 and H3K27me3 marks at potential PREs in Drosophila and mammalian cells.
• Investigated gene expression changes in MLL1-deficient and PRC2-inhibited cells.
• Correlated epigenetic marks with gene activity to define functional PREs.

Main Results:

• Demonstrated that Trx-dependent H3K4me2 marks Drosophila PREs and maintains developmental gene expression.
• Showed that mammalian MLL1 deposits H3K4me2 at CpG-dense regions, potentially serving as PREs.
• Revealed that H3K27me3 levels increase at these loci in the absence of MLL1, and PRC2 inhibition rescues gene expression.

Conclusions:

• MLL1-deposited H3K4me2 serves as a key mark for functional mammalian PREs.
• A functional balance exists between MLL1 and PRC2 activities in regulating gene expression at these sites.
• Provided rules for identifying cell-type-specific functional mammalian PREs within the human genome.