Each of our cells contains a lot of DNA. So much DNA, in fact, that it has to be elaborately condensed and organized into chromosomes, which are then packed into the cell’s nucleus. If completely unraveled, the genetic material from just one of our 46 chromosomes would stretch out to 1.5 centimeters – 10,000 times the length of the packed chromosome.To condense all of this genetic material, long strands of DNA are tightly wound around proteins called histones. All this packing, however, can present a problem when our cellular machinery needs to access our DNA to read genes and produce proteins. As a result, chromosome packing is dynamic – some areas stay tightly wound while others are looser. Just how accessible a particular region is can vary, depending on the tissue type, stage of development, disease state and other factors.
Dr. Sepideh Khorasanizadeh, one of Sanford-Burnham’s newest faculty members in Lake Nona, Florida, studies the cellular signals that influence chromosome packing to turn genes on and off. While much is known about how cells receive signals from the environment and carry those signals across into the cytoplasm, what happens when they reach the nucleus remains a mystery.
“Cell signaling enters a black box when it reaches the nucleus,” Dr. Khorasanizadeh said. “If we could fill in the gaps – that would be our dream.”
One chromosomal clue Dr. Khorasanizadeh is studying is lysine methylation. She’s found that, in places where cells need quick access to DNA, histones are often tagged with a methyl group on one particular amino acid (lysine). This signal seems to be specific to the nucleus, where it entices cellular machinery to loosen the chromosomes and begin gene transcription – the first step in translating genetic information into a protein.
According to Dr. Khorasanizadeh, lysine methylation lets the gene transcription machinery know what region of the chromosome to target. She thinks of it like Goldilocks: the cell scans the chromosome looking for just the right structure (which includes methylated lysines) before settling down to do its job.
“Lysine methylation is a mechanism for the system to say ‘don’t go there, the chromatin doesn’t look good… But here this fiber looks just right’,” Dr. Khorasanizadeh explained. “Here is a methylated histone that I can bind to in order to bring the right enzyme machinery and open up the chromatin just enough to allow for gene transcription.”
Unraveling chromosomes to turn genes on and off could be studied in any type of cell, but as a professor in Sanford-Burnham’s Metabolic Signaling and Disease Program, Dr. Khorasanizadeh plans to focus on tissues that contribute to diabetes and cardiovascular health. After spending more than a decade studying chromosomes, packing in a lot just comes naturally to her.
“I’m very happy to be here at Sanford-Burnham,” she said. “I just wish I could fit 10 more hours in the day!”