When it comes to cell differentiation, it’s all about location, according to a new study from the Perelman School of Medicine at the University of Pennsylvania. The study found that the ability of a stem cell to differentiate into distinct cell types depends on what portions of the genome are available for activation based on the positioning of the DNA in a cell’s nucleus.
The scientists wanted to understand how a cell responds to molecular clues to know what type of cell to become. What they found is that some regions of the genome are tightly packed against the inner membrane of the cell nucleus (the lamina), effectively silencing the gene. These sequestered regions help define a cell’s identity by dictating what the particular cell will not become.
The team found an epigenetic enzyme called histone deacetylase (Hdac3) tethers DNA to the nuclear periphery. When they removed Hdac3 in stem cells during heart cell differentiation, regions of DNA containing heart-specific genes became untethered, allowing for activation of these genes and leading to overly fast differentiation.
"The implications of this study are far-reaching," co-senior author Jonathan A. Epstein, M.D. "The ability to control how quickly a cell differentiates to make cardiac tissue or other cell types has important implications for regenerative medicine." This could also have important implications for cancer research as cancer can cause some genes to be abnormally expressed, thus changing their identity.
This study may also have applications for the study of competency as it’s possible that differences in competency may be due to the availability of certain genes.
The team plans to continue investigating this phenomenon and determine what role genes at the nuclear periphery play in cancer and other disease susceptibility.
Image: Cell fate determination requires the coordinated regulation of gene programs involved in development and the maturation of tissues. The team found that Hdac3 influences cell fate determination through its role as a tether that coordinates the three-dimensional organization of chromatin in the nucleus. The illustration (left) represents the interior of the nucleus where individual cell fate is determined by which gene programs are available, while others are stored away in an inaccessible molecular closet. The right image is a 3D representation of the location of the Titin gene (red) in a cardiac myocyte. Image courtesy of Kate Isenberg.