WASHINGTON, DC – (April 20, 2016)
– Very subtle changes in just a single component of the nuclear envelope – the part of a person’s cell that helps to regulate gene expression – can dramatically change which DNA the cell chooses to cast aside as it does housekeeping and which DNA the cell keeps active and on call for future use.
The seemingly small change can lead to a cascade of cellular misadventures since it comes at a crucial time, when dividing cells adopt specialized roles within the body becoming, for example, nerves, the heart, or muscles.
“Cells become confused as to what they should be,” says Eric P. Hoffman, PhD, a geneticist who has directed the Center for Genetic Medicine Research
at Children’s National Health System and who was senior author of the paper published online April 20 in Science Translational Medicine
. “Individual mutations then influence different cells in different ways. Some cause muscles to become confused. Some cause fat cells to become confused,” Dr. Hoffman continues.
The international team, led by Children’s National research scientists, was interested in learning more about one single gene, lamin A/C (LMNA), which is to blame for a multitude of genetic disorders, such as premature aging and problems with nerves, the heart, and muscles.
“It has been quite disorienting to the scientific and medical community as to why subtle changes of the same gene cause such dramatically different disorders,” says Dr. Hoffman, who in mid-April left Children’s National to join Binghamton University, State University of New York.
Specifically, the research team wanted to better understand Emery-Dreifuss muscular dystrophy, a condition that is first felt by restricting movement in certain joints, such as the ankles, elbows, and neck, and that can lead to progressive muscle weakness in childhood and heart problems by adulthood.
Proper cell differentiation hinges on “the coordinated execution of three key cellular programs,” the study’s lead author, Jelena Perovanovic, PhD, also of Children’s Center for Genetic Medicine Research, and colleagues write. Pluriopotency programs, which give primitive cells the remarkable ability to generate any cell type in the body, are inactivated. Exit from the cell cycle occurs, and cells stop dividing. Myogenesis is induced, ushering in formation of muscle tissue.
When mutations occur in LMNA as well as the nuclear membrane protein emerin (EMD), this careful cellular choreography can go awry.
“[O]ur data suggest that, in the presence of LMNA and EMD mutations and, by extension, all nuclear envelope disorders, there is inappropriate association of heterochromatin with nuclear lamina upon differentiation,” Perovanovic and co-authors write. “This mishap results in three parallel events that may have a cumulative effect: slowing of exit from cell cycle … slowing of exit from pluripotency programs … and poorly coordinated induction of terminal differentiation programs.”
The research team provides “a unifying model for this process” and an explanation for how subtle mutations of LMNA play a particularly disruptive role.
“Different parts of the genome need to become attached to the outside of the nucleus. The nuclear envelope, an essential structure that distinguishes creatures that grow organs from bacteria, is the place where these attached regions are pulled from genetic circulation never to be used again,” Dr. Hoffman explains. “In a way, the process of attachment signals which parts of the genome the cell no longer considers useful. The act of discarding superfluous DNA keeps the cell focused on what matters more: Its future role, be it as a heart cell, a nerve cell, a muscle cell, or something else.”
Contact: Diedtra Henderson at 202-476-4500
Related: Research at a Glance - Why subtle cellular changes can result in dramatically different genetic disorders