In this schematic of a chromosome’s 3D structure, the DNA loops (black) are anchored by CTCF proteins (purple) at their bases. Regulatory elements, called enhancers (red) only affect the genes (black arrows) that reside in the loops with them. The protein cohesin (blue rings) forms the looped structures. Credit: Courtesy of Cell Press
A map has been created of the DNA loops that comprise 3D structure of the human genome and contribute to gene regulation in human embryonic stem cells. The location of genes and regulatory elements within this chromosomal framework will help scientists better navigate their genomic research, establishing relationships between mutations and disease development.
This is transformational,” says Whitehead Member Richard Young. “This map allows us to predict how genes are regulated in normal cells, and how they are misregulated in disease, with far greater accuracy than before.”
In order to regulate gene expression, a regulatory element needs to contact its target gene. Through looping, element/gene partners that are distant from each other in linear DNA can be brought together. Most disease mutations occur in regulatory elements, but if the partnership between a seemingly far-flung gene and the regulatory element is not known, the mutation data is of limited use. This draft map, which can help scientists predict the relationships between mutated elements and their target genes, is described online in the journal Cell Stem Cell.
Previous research in mouse ES cells by Young’s lab and others determined that a chromosome’s DNA is formed into loops that are anchored at their bases by proteins called CTCFs. The benefits of the loops are two-fold. First, the loops help organize and package 2m of DNA to fit into a nucleus that is approximately 5 micrometers in diameter. Second, each loop creates an insulated neighborhood that restricts the action of a regulatory element to genes that resides in the same loop. Diego Borges-Rivera states, “The genome’s 3D shape is a key mechanism underlying gene regulation.”
By studying human ES cells, scientists in the Young lab and the lab of Whitehead Founding Member Rudolf Jaenisch created an initial genome map consisting of 13,000 loops established by CTCF anchors and determined that the average insulated neighborhood is 200 kb in length and contains a single gene. The team found most of the the mapped CTCF anchor sites in the human ES cells genome are maintained in other human cell types and these loop anchor sequences are highly conserved in primate genomes. Such a surprising degree of conservation indicates that these neighborhoods create a foundational framework for gene regulation that is maintained throughout development and across species.
TCTCF anchor regions are mutated in a broad spectrum of cancer cells. The team predicts that these new maps of the human genome will provide the foundation for improved understanding of the genetic alterations that cause many additional diseases. http://wi.mit.edu/news/archive/2015/3d-map-human-genome-reveals-relationship-between-mutations-and-disease-development
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