When a cell is well oxygenated and well nourished, DNA stays loose and loopy. But when a cell is deprived of oxygen and nutrients, DNA retreats into itself, compacting into tight clusters, as though it were crouching within a bunker, hoping to outlast lean times. Essentially, DNA goes into survivalist mode. Even so, DNA is never so sequestered as to escape the scrutiny of curious scientists.
The latest peek inside the DNA bunker has been taken by scientists of the Institute of Molecular Biology (IMB) in Mainz. They took advantage of a technique called single-molecule localization microscopy, a form of super-resolution light microscopy that uses blinking dyes that bind to DNA to enable researchers to define the location of individual molecules in cells. With this technique and other methods, the IMB scientists gained new insight into DNA’s hunkered-down state, which typically occurs when cells are deprived of adequate blood supply, during episodes of heart attack and stroke, for example.
The scientists presented their results November 5 in the journal Genome Biology, in an article entitled, “A transient ischemic environment induces reversible compaction of chromatin.”
“Short-term oxygen and nutrient deprivation of the cardiomyocyte cell line HL-1 induces a previously undescribed chromatin architecture, consisting of large, chromatin-sparse voids interspersed between DNA-dense hollow helicoid structures 40–700 nm in dimension,” wrote the authors. “The chromatin compaction is reversible, and upon restitution of normoxia and nutrients, chromatin transiently adopts a more open structure than in untreated cells.”
The scientists found that the compacted state of chromatin reduces transcription, whereas the open chromatin structure induced upon recovery provokes a transitory increase in transcription. Confirming these results, the scientists determined that condensed chromatin exhibits an increased resistance to digestion with DNAseI compared with chromatin in untreated cells and, additionally, that the mobility of linker histone H1, as estimated by fluorescent recovery after photobleaching (FRAP), is significantly reduced by oxygen and nutrient deprivation.
“When you have a stroke, when you have a heart attack, this is likely to be what's happening to your DNA,” explained George Reid, Ph.D., one of the IMB scientists and a senior author of the Genome Biology paper. “Now we know that this is what's going on, we can start to look at ways of preventing this compaction of DNA.”
According to the IMB scientists, the extent and reversibility of chromatin compaction induced by oxygen and nutrient deprivation suggests that the impact of ischemia could be constrained by targeting biochemical events that are required for chromatin condensation. To some extent, these events are already being targeted in preclinical studies. For example, animal studies are evaluating the potential benefits of inhibiting histone deacetylase activity.
Alternative approaches, however, may open up now that additional details of DNA compaction are becoming available. One such detail, uncovered in the current study, is that ischemic conditions lower intracellular ATP levels, resulting in the redistribution of the intracellular polyamine pool into the nucleus and inducing a large reduction in the rate of synthesis of RNA.
“Defining and understanding these effects,” the authors noted, “offers a diverse range of tractable targets for therapeutic intervention in human disease.” The authors also speculated that the transient adoption of unusually open chromatin architectures upon ischemic recovery could leave cells more susceptible to epigenetic reprogramming.