21 research outputs found
MicroRNA Genes Derived from Repetitive Elements and Expanded by Segmental Duplication Events in Mammalian Genomes
MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene
expression by targeting mRNAs for translation repression or mRNA degradation.
Many miRNAs are being discovered and studied, but in most cases their origin,
evolution and function remain unclear. Here, we characterized miRNAs derived
from repetitive elements and miRNA families expanded by segmental duplication
events in the human, rhesus and mouse genomes. We applied a comparative genomics
approach combined with identifying miRNA paralogs in segmental duplication pair
data in a genome-wide study to identify new homologs of human miRNAs in the
rhesus and mouse genomes. Interestingly, using segmental duplication pair data,
we provided credible computational evidence that two miRNA genes are located in
the pseudoautosomal region of the human Y chromosome. We characterized all the
miRNAs whether they were derived from repetitive elements or not and identified
significant differences between the repeat-related miRNAs (RrmiRs) and
non-repeat-derived miRNAs in (1) their location in protein-coding and intergenic
regions in genomes, (2) the minimum free energy of their hairpin structures, and
(3) their conservation in vertebrate genomes. We found some lineage-specific
RrmiR families and three lineage-specific expansion families, and provided
evidence indicating that some RrmiR families formed and expanded during
evolutionary segmental duplication events. We also provided computational and
experimental evidence for the functions of the conservative RrmiR families in
the three species. Together, our results indicate that repetitive elements
contribute to the origin of miRNAs, and large segmental duplication events could
prompt the expansion of some miRNA families, including RrmiR families. Our study
is a valuable contribution to the knowledge of evolution and function of
non-coding region in genome
DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity
Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity
Dietary heme induces acute oxidative stress, but delayed cytotoxicity and compensatory hyperproliferation in mouse colon
Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by generating cytotoxic and oxidative stress. Recently, we found that this surface injury is compensated by hyperproliferation and hyperplasia of crypt cells, which was induced by a changed surface to crypt signaling. It is unknown whether this changed signaling is caused by cytotoxic stress and/or oxidative stress, as these processes were never studied separately. The aim of this study was to determine the possible differential effects of dietary heme on these luminal stressors and their impact on the colonic mucosa after 2, 4, 7 and 14 days of heme feeding. Mice received a purified, humanized, control diet or the diet supplemented with 0.2 µmol heme/g. Oxidative and cytotoxic stress were measured in fecal water. Proliferation was determined by Ki67-immunohistochemistry and mucosal responses by whole-genome transcriptomics. After heme ingestion, there was an acute increase in reactive oxygen species (ROS) leading to increased levels of lipid peroxidation products. Mucosal gene expression showed an acute antioxidant response, but no change in cell turnover. After day 4, cytotoxicity of the colonic contents was increased and this coincided with differential signaling and hyperproliferation, indicating that cytotoxicity was the causal factor. Simultaneously, several oncogenes were activated, whereas the tumor suppressor p53 was inhibited. In conclusion, luminal cytotoxicity, but not ROS, caused differential surface to crypt signaling resulting in mucosal hyperproliferation and the differential expression of oncogenes and tumor suppressor genes