Salk scientists and collaborators have shed light on a long-standing question about what leads to variation in stem cells simply by comparing induced pluripotent stem cells (iPSCs) derived from similar twins. Even iPSCs made from the cells of twins, these people found, have important differences, suggesting that not all alternative between iPSC lines is rooted in genetics, because the twins have identical genes.
Because they can differentiate into almost any cell type in your body, stem cells have the potential to be used to create healthy tissue to treat a number of diseases. But stem cells come in 2 varieties: embryonic stem cells (ESCs), which are isolated through embryos, and iPSCs, which are created in the lab through adult cells that are reprogrammed using mixtures of signaling molecules and are a promising tool for understanding disease plus developing new treatments.
Although iPSCs look like ESCs in most ways, scientists have found that iPSCs frequently have variations in their epigenetics — methyl marks on the GENETICS that dictate when genes are expressed. These epigenetic markers aren’t the same between iPSCs and ESCs, as well as between different lines of iPSCs. In the past, it’s been difficult to determine what drives these differences.
“When all of us reprogram cells, we see small differences when we evaluate them to stem cells that come from an embryo. All of us wanted to understand what types of differences are always there, what is causing all of them, and what they mean, ” says Juan Carlos Izpisua Belmonte, a professor in Salk’s Gene Expression Lab and co-senior author, with Kelly Frazer of the College of California, San Diego, on the new paper, which was released in Cell Stem Cell in April 2017. A better understanding of these differences can help researchers refine stem-cell based treatments for disease.
Izpisua Belmonte and Frazer, along with co-first writers of the paper Athanasia Panopoulos, formerly a postdoctoral many other at Salk and now at the University of Notre Dame, and Erin Smith of UCSD, turned to twins to assist sort it out.
Although identical baby twins have the same genes as each other, their epigenomes — the collection of methyl marks studding their DNA — are different by the time they reach adulthood due in part in order to environmental factors. Reprogramming the skin cells of adult similar twins to their embryonic state eliminated most of these differences, the particular researchers found when they studied cells from three models of twins. However , there were still key epigenetic variations between twins in terms of how the iPSCs compared to ESCs.
When the team looked more in depth at the places of the genome where this variation between methyl signifies tended to show up in twins, they found they often fell near binding sites for a regulatory proteins called MYC.
“In the past, researchers acquired found lots of sites with variations in methylation position, but it was hard to figure out which of those sites acquired variation due to genetics, ” says Panopoulos. “Here, we’re able to focus more specifically on the sites we know have absolutely nothing to do with genetics. ” That new focus, she states, is what allowed them to home in on the MYC joining sites.
The MYC protein — that is one of the molecules used to reprogram iPSCs from adult cellular material — likely plays a role in dictating which sites in the genome are randomly methylated during the reprogramming process, the scientists hypothesized.
“The twins enabled us in order to ask questions we couldn’t ask before, ” says Panopoulos. “You’re able to see what happens when you reprogram cells along with identical genomes but divergent epigenomes, and figure out what is going on because of genetics, and what is happening due to other mechanisms. inch
The findings help scientists better be familiar with processes involved in reprogramming cells and the differences between iPSCs and ESCs, which has implications on future studies planning to understand the specific causes and consequences of these changes, as well as the way iPSCs are being used for research and therapeutics.
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