38 research outputs found
Hypomethylation of Intragenic LINE-1 Represses Transcription in Cancer Cells through AGO2
In human cancers, the methylation of long interspersed nuclear element -1 (LINE-1
or L1) retrotransposons is reduced. This occurs within the context of genome
wide hypomethylation, and although it is common, its role is poorly understood.
L1s are widely distributed both inside and outside of genes, intragenic and
intergenic, respectively. Interestingly, the insertion of active full-length L1
sequences into host gene introns disrupts gene expression. Here, we evaluated if
intragenic L1 hypomethylation influences their host gene expression in cancer.
First, we extracted data from L1base (http://l1base.molgen.mpg.de), a database containing putatively
active L1 insertions, and compared intragenic and intergenic L1 characters. We
found that intragenic L1 sequences have been conserved across evolutionary time
with respect to transcriptional activity and CpG dinucleotide sites for
mammalian DNA methylation. Then, we compared regulated mRNA levels of cells from
two different experiments available from Gene Expression Omnibus (GEO), a
database repository of high throughput gene expression data, (http://www.ncbi.nlm.nih.gov/geo) by chi-square. The odds ratio
of down-regulated genes between demethylated normal bronchial epithelium and
lung cancer was high (p<1E−27;
OR = 3.14; 95%
CI = 2.54–3.88), suggesting cancer genome wide
hypomethylation down-regulating gene expression. Comprehensive analysis between
L1 locations and gene expression showed that expression of genes containing L1s
had a significantly higher likelihood to be repressed in cancer and
hypomethylated normal cells. In contrast, many mRNAs derived from genes
containing L1s are elevated in Argonaute 2 (AGO2 or EIF2C2)-depleted cells.
Hypomethylated L1s increase L1 mRNA levels. Finally, we found that AGO2 targets
intronic L1 pre-mRNA complexes and represses cancer genes. These findings
represent one of the mechanisms of cancer genome wide hypomethylation altering
gene expression. Hypomethylated intragenic L1s are a nuclear siRNA mediated
cis-regulatory element that can repress genes. This
epigenetic regulation of retrotransposons likely influences many aspects of
genomic biology
Bioinformatic and statistical analysis of the optic nerve head in a primate model of ocular hypertension
<p>Abstract</p> <p>Background</p> <p>The nonhuman primate model of glaucomatous optic neuropathy most faithfully reproduces the human disease. We used high-density oligonucleotide arrays to investigate whole genome transcriptional changes occurring at the optic nerve head during primate experimental glaucoma.</p> <p>Results</p> <p>Laser scarification of the trabecular meshwork of cynomolgus macaques produced elevated intraocular pressure that was monitored over time and led to varying degrees of damage in different samples. The macaques were examined clinically before enucleation and the myelinated optic nerves were processed post-mortem to determine the degree of neuronal loss. Global gene expression was examined in dissected optic nerve heads with Affymetrix GeneChip microarrays. We validated a subset of differentially expressed genes using qRT-PCR, immunohistochemistry, and immuno-enriched astrocytes from healthy and glaucomatous human donors. These genes have previously defined roles in axonal outgrowth, immune response, cell motility, neuroprotection, and extracellular matrix remodeling.</p> <p>Conclusion</p> <p>Our findings show that glaucoma is associated with increased expression of genes that mediate axonal outgrowth, immune response, cell motility, neuroprotection, and ECM remodeling. These studies also reveal that, as glaucoma progresses, retinal ganglion cell axons may make a regenerative attempt to restore lost nerve cell contact.</p
Wound dressings for a proteolytic-rich environment
Wound dressings have experienced continuous and significant changes over the years based on the knowledge of the biochemical events associated with chronic wounds. The development goes from natural
materials used to just cover and conceal the wound to interactive materials that can facilitate the healing process, addressing specific issues in non-healing wounds. These
new types of dressings often relate with the proteolytic wound environment and the bacteria load to enhance the healing. Recently, the wound dressing research is focusing on the replacement of synthetic polymers by natural protein materials to delivery bioactive agents to the wounds. This
article provides an overview on the novel protein-based wound dressings such as silk fibroin keratin and elastin.
The improved properties of these dressings, like the release of antibiotics and growth factors, are discussed. The different types of wounds and the effective parameters of
healing process will be reviewed
Macrophage secretion of miR-106b-5p causes renin-dependent hypertension
Myeloid cells are known mediators of hypertension, but their role in initiating renin-induced hypertension has not been studied. Vitamin D deficiency causes pro-inflammatory macrophage infiltration in metabolic tissues and is linked to renin-mediated hypertension. We tested the hypothesis that impaired vitamin D signaling in macrophages causes hypertension using conditional knockout of the myeloid vitamin D receptor in mice (KODMAC). These mice develop renin-dependent hypertension due to macrophage infiltration of the vasculature and direct activation of renal juxtaglomerular (JG) cell renin production. Induction of endoplasmic reticulum stress in knockout macrophages increases miR-106b-5p secretion, which stimulates JG cell renin production via repression of transcription factors E2f1 and Pde3b. Moreover, in wild-type recipient mice of KODMAC/miR106b-/- bone marrow, knockout of miR-106b-5p prevents the hypertension and JG cell renin production induced by KODMAC macrophages, suggesting myeloid-specific, miR-106b-5p-dependent effects. These findings confirm macrophage miR-106b-5p secretion from impaired vitamin D receptor signaling causes inflammation-induced hypertension.status: publishe