Regulation of nuclear transcription by mitochondrial RNA in endothelial cells.
Publication Year:
2024
PubMed ID:
38251974
Public Summary:
Inside our cells, tiny molecules called RNAs help control how genes are turned on and off. Most of these RNAs come from the cell's nucleus, where our main DNA is stored. However, we found that some RNAs made in the mitochondria—the cell’s “power plants”—can also attach to DNA in the nucleus. We call these mitochondrial RNAs that link up with nuclear DNA “mt-caRNAs.”
In our study, we found that mt-caRNAs tend to attach to DNA areas that control other genes, especially in cells exposed to stress similar to that in diabetes. When we blocked a certain mt-caRNA in cells that line blood vessels, it stopped some of the gene changes caused by stress and prevented unhealthy interactions between these cells and immune cells—something commonly seen in diabetes. We also observed that in cells from people with diabetes, more mtRNAs were moving to the nucleus, suggesting this may happen as part of the body’s response to stress or disease.
Our research suggests that mt-caRNAs may be a way for mitochondria to “talk” to the nucleus, linking the energy centers of the cell directly with how genes are controlled. This discovery could help us better understand diseases like diabetes and how different parts of the cell work together in response to stress.
Scientific Abstract:
Chromatin-associated RNAs (caRNAs) form a relatively poorly recognized layer of the epigenome. The caRNAs reported to date are transcribed from the nuclear genome. Here, leveraging a recently developed assay for detection of caRNAs and their genomic association, we report that mitochondrial RNAs (mtRNAs) are attached to the nuclear genome and constitute a subset of caRNA, thus termed mt-caRNA. In four human cell types analyzed, mt-caRNAs preferentially attach to promoter regions. In human endothelial cells (ECs), the level of mt-caRNA-promoter attachment changes in response to environmental stress that mimics diabetes. Suppression of a non-coding mt-caRNA in ECs attenuates stress-induced nascent RNA transcription from the nuclear genome, including that of critical genes regulating cell adhesion, and abolishes stress-induced monocyte adhesion, a hallmark of dysfunctional ECs. Finally, we report increased nuclear localization of multiple mtRNAs in the ECs of human diabetic donors, suggesting many mtRNA translocate to the nucleus in a cell stress and disease-dependent manner. These data nominate mt-caRNAs as messenger molecules responsible for mitochondrial-nuclear communication and connect the immediate product of mitochondrial transcription with the transcriptional regulation of the nuclear genome.
