Penn investigators are discovering ways in which epigenetics not only tell a cell what it will become – a liver or pancreas cell, for example – but also how to do it.

Biologists have spent decades working to decipher what makes one cell in an embryo take on one fate versus another. Already they know that things like location within the developing embryo can influence the decision, as can signals from nearby cells. In the last couple of years, Kenneth S. Zaret, PhD, of Cell and Developmental Biology and associate director of the Penn Institute for Regenerative Medicine, and colleagues have found that some of the earliest cellular decision-making occurs at the level of chromatin.

DNA winds around histones proteins, and the cell can control which genes are turned on or off by how tightly wound the DNA-histone package is. Pancreas and liver cells come from the same lineage. Zaret's group found that as progenitor cells start along the path of choosing one fate or the other, enzymes modify the histones bound to different chromosomal regions, essentially silencing those genes. Thus, even before outside signals start to tell a cell to be a liver or pancreas cell, signals in the chromatin are already pushing it in one direction or the other.

In a related set of studies, Zaret's team has focused on embryonic-like stem cells. A key hope of regenerative medicine is the idea that clinicians might be able to induce already differentiated cells into becoming stem cells, which could then be used to regenerate damaged or diseased tissues. Researchers have developed such techniques, but the process is very inefficient. Recently, Zaret's team reported that some of that inefficiency is due to the sluggishness of epigenetic reprogramming at certain regions of the genome.

These refractory sequences tended to be chemically marked with a histone modification called H3K9me3. When the team blocked the enzymes that create that modification, they significantly accelerated the reprogramming process.  The new insights might lead to more efficient production of embryonic-like stem cells, and eventually new approaches to regenerative medicine.

Turning off or down gene expression is a common theme in epigenetics, often controlled by enzymes that either mark or erase marks on histone proteins. A team led by Mitchell A. Lazar, MD, PhD, director of the Institute for Diabetes, Obesity, and Metabolism, has been studying HDAC3 for several years. They discovered that the enzyme activity of HDAC3 requires interaction with a specific region on another protein, which they dubbed the Deacetylase Activating Domain or "DAD.” This “nuts and bolts” discovery on the epigenetic control of a person’s genome has implications for cancer and neurological treatments, which are starting to rely more and more on controlling epigenetic gene regulation.

Another fundamental area of cell biology is the study of cell division. During cell division, thread-like proteins called microtubules extend from the two poles of the cell to the center of the chromosomes. One of the key proteins that connects the microtubules and the chromosomes is called CENP-A. Recently, Ben E. Black, PhD, associate professor of Biochemistry and Biophysics, and colleagues reported that CENP-A marks the site of microtubule binding, called the centromere, by altering the structure of the nucleosomes and thus the shape of the chromatin itself.

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