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Three-Dimensional Genome Mapping Method Provides Insights Into Chromosomal Organization

NEW YORK (GenomeWeb)  ̶  Just in time for the holidays, an international team led by researchers at the Jackson Laboratory for Genomic Medicine has used 3D genome mapping to determine that certain protein factors organize chromosomes inside the cell nucleus in three dimensions, "forming a shape like a gift bow."

Loops of DNA that look like ribbon loops are held by proteins that aggregate into a "central knot," the team said in a statement. When genes are properly expressed, the bow is neat and organized, the researchers added. But in the presence of certain mutations, the bow becomes "a tangled mess."

"The significance of this paper lies in our advanced 3D genome mapping strategy," said senior author and Jackson Lab professor Yijun Ruan in a statement. It "allowed us to reveal, for the first time, the higher-order and detailed topological structures of the human genome mediated by CTCF and cohesin, and the relation to gene transcription regulation carried out by RNA polymerase II."

As they reported today in Cell, the researchers comprehensively mapped higher-order chromosome folding and specific chromatin interactions mediated by CTCF and RNAPII in different human cell lineages using chromatin interaction analysis by paired-end tag sequencing (ChIA-PET). They determined that constitutive genes organize themselves around CTCF- and cohesin-mediated interaction anchors, and that RNAPII then draws cell-type-specific genes towards these central anchors for coordinated transcription.  

"For instance, 'housekeeping genes' were often found near the protein-bound knots, whereas cell-specific genes were more commonly positioned in the extended DNA loops," the team's statement said.

Further, the team's 3D genome simulation showed that chromosome configuration, including gene expression, is differentially affected by haplotype variants and allelic interaction. This suggests a possible mechanistic link between certain diseases and mutations.

"3D genome simulation suggests a model of chromatin folding around chromosomal axes, where CTCF is involved in defining the interface between condensed and open compartments for structural regulation. Our 3D genome strategy thus provides unique insights in the topological mechanism of human variations and diseases," the researchers wrote.

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