Genome-Wide Transcriptional Analysis Reveals the Protection against Hypoxia-Induced Oxidative Injury in the Intestine of Tibetans via the Inhibition of GRB2/EGFR/PTPN11 Pathways

The molecular mechanisms for hypoxic environment causing the injury of intestinal mucosal barrier (IMB) are widely unknown. To address the issue, Han Chinese from 100 m altitude and Tibetans from high altitude (more than 3650 m) were recruited. Histological and transcriptome analyses were performed. The results showed intestinal villi were reduced and appeared irregular, and glandular epithelium was destroyed in the IMB of Tibetans when compared with Han Chinese. Transcriptome analysis revealed 2573 genes with altered expression. The levels of 1137 genes increased and 1436 genes decreased in Tibetans when compared with Han Chinese. Gene ontology (GO) analysis indicated most immunological responses were reduced in the IMB of Tibetans when compared with Han Chinese. Gene microarray showed that there were 25-, 22-, and 18-fold downregulation for growth factor receptor-bound protein 2 (GRB2), epidermal growth factor receptor (EGFR), and tyrosine-protein phosphatase nonreceptor type 11 (PTPN11) in the IMB of Tibetans when compared with Han Chinese. The downregulation of EGFR, GRB2, and PTPN11 will reduce the production of reactive oxygen species and protect against oxidative stress-induced injury for intestine. Thus, the transcriptome analysis showed the protecting functions of IMB patients against hypoxia-induced oxidative injury in the intestine of Tibetans via affecting GRB2/EGFR/PTPN11 pathways

Transcriptome Reveals 1400-Fold Upregulation of APOA4-APOC3 and 1100-Fold Downregulation of GIF in the Patients with Polycythemia-Induced Gastric Injury.

High-altitude polycythemia (HAPC) inducing gastric mucosal lesion (GML) is still out of control and molecular mechanisms remain widely unknown. To address the issues, endoscopy and histopathological analyses were performed. Meanwhile, microarray-based transcriptome profiling was conducted in the gastric mucosa from 3 pairs of healthy subjects and HAPC-induced GML patients. HAPC caused morphological changes and pathological damages of the gastric mucosa of GML patients. A total of 10304 differentially expressed genes (DEGs) were identified, including 4941 up-regulated and 5363 down-regulated DEGs in gastric mucosa of GML patients compared with healthy controls (fold change ≥2, P<0.01 and FDR <0.01). Particularly, apolipoprotein genes APOA4 and APOC3 were 1473-fold and 1468-fold up-regulated in GML patients compared with the controls. In contrast, gastric intrinsic factor (GIF) was 1102-fold down-regulated in GML patients compared with the controls. APOA4 (chr11:116691770-116691711), APOC3 (chr11:116703530-116703589) and GIF (chr11:59603362-59603303) genes are all located on chromosome 11. APOA4 and APOC3 act as an inhibitor of gastric acid secretion while gastric acid promotes ulceration. GIF deficiency activates a program of acute anemia, which may antagonize polycythemia while polycythemia raises the risk of GML. Therefore, the present findings reveal that HAPC-induced GML inspires the protection responses by up-regulating APOA4 and APOC3, and down-regulating GIF. These results may offer the basic information for the treatment of HAPC-induced gastric lesion in the future

Highly TOP down-regulated genes in GML patients in comparison with controls.

<p>Highly TOP down-regulated genes in GML patients in comparison with controls.</p

Gene ontology (GO) analysis used for analysis of the altered genes.

<p>A, The bar plot showed the top ten up-regulated Enrichment Score values of the significant enrichment; B, The bar plot showed the top ten down-regulated Enrichment Score values of the significant enrichment BP.</p

Pathway analysis of DEG.

<p>A: The bar plot showed the top ten up-regulated Enrichment Score values of the significant enrichment pathway; B: The bar plot showed the top ten down-regulated Enrichment Score value of the significant enrichment pathway.</p

Validating microarray results using qRT-PCR.

<p>A, the top-4 up-regulated DEGs. B, the top-4 down-regulated DEGs. The results represented quantification of mRNA levels relative to β-actin. Normalized expression values were obtained by qRT-PCR (n = 3). C = Controls, P = GML patients.</p

Histopathological examination of gastric mucosa sections.

<p>A, Hematoxylin-eosin stained results showed appearance of the gastric mucosa in antrum region of the control group and HAPC-induced GML group (× 40 and × 400); B, The gastric mucosal damage score in control and HAPC-induced GML group. The mean scores were significantly higher in the HAPC-induced GML group when compared with a control group (P < 0.01, n = 3 per group).</p

Sequencing of 50 human exomes reveals adaptation to high altitude

Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exornes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18x per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1), a transcription factor involved in response to hypoxia. One single-nucleotide polymorphism (SNP) at EPASl shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP's association with erythrocyte abundance supports the role of EPASl in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude. Copyright 2010 by the American Association for the Advancement of Science; all rights reserved.Link_to_subscribed_fulltex

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