*Newswise—BOSTON, MA—May 14, 2018**—A new study from Harvard Medical School helps to explain an enduring mystery of human genetics. Some parts of our DNA encode crucial instructions that are essential for life. These sequences tend to be repeated throughout our genome, which helps safeguard against damaging mutations. But another major class of essential genes, those encoding proteins that control when and where other genes are turned on or off, have long proved puzzling to scientists. These regulatory sequences are generally found only once in the genome, yet mutations that alter their function can cause disease or even death.
Now, researchers show in the May 14 issue of the journal Cell, that nature has evolved a creative way of safeguarding these crucial genes. They identified genomic regions that contain multiple distinct regulatory elements, each essential for embryonic development, packed tightly together into a single regulatory module.
“It appears that nature has chosen to put multiple regulatory elements into one location and rely on the physical structure of the chromosome to protect them as a unit,” said Eric Heard, HMS professor of genetics and senior author of the study.
Heard’s team focused on a region of human chromosome 1 that contains numerous regulatory elements, essential for life, controlling the activity of the HoxD gene cluster. The HoxD genes are known to be crucial regulators of embryonic development, controlling how the embryo forms along its front-to-back axis.
The team used a variety of techniques to show that the region containing the HoxD regulatory elements forms a physical loop in the chromosome. This looping structure brings together distinct regulatory elements and enables them to work together to control the activity of the HoxD genes.
The researchers also created mice with mutations in the DNA sequence within this regulatory loop. They found that some of these mutations, in the regulatory elements controlling HoxD, were incompatible with life. Other mutations, farther from the HoxD genes but within the loop, reduced HoxD activity or caused other severe developmental problems.
The structure of this regulatory loop provides an explanation for why these DNA sequences with critical regulatory functions are found only once in the human genome, said Heard.
"When something is really important for life, nature often has backups,” he said. “For these particular DNA elements, nature has packaged multiple essential functions next to each other to take advantage of the protective nature of the chromosome.”
The research sheds light on a number of genomic disorders that may be due to mutations in these complex regulatory regions.
The study was funded by the National Institutes of Health (NIH). Co-authors included first author Thomas Sexton, a PhD student in the Harvard/MIT Division of Health Sciences and Technology; John Cavalli, a Harvard Medical School research fellow; and researchers from the University of Geneva.
Written by:
Alexandra Stern
