Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Long-term adaptation to hypoxic conditions - Febit transcriptome analysis

ABSTRACT: Aspergillus fumigatus is an opportunistic, airborne pathogen causing invasive aspergillosis in immunocompromised patients. During the infection process A. fumigatus is challenged by hypoxic microenvironments occurring in inflammatory, necrotic tissue. To gain further insights into the adaptation mechanism, A. fumigatus was cultivated in an oxygen-controlled chemostat under hypoxic and normoxic conditions. Transcriptome analysis revealed significant increases in transcripts associated with cell wall polysaccharide metabolism, amino acid and metal ion transport, nitrogen metabolism and glycolysis. A concomitant reduction in transcript levels was observed with cellular trafficking and G-protein coupled signaling. To learn more about the functional roles of hypoxia-induced transcripts we deleted A. fumigatus genes putatively involved in reactive nitrogen species detoxification (fhpA), NAD+ regeneration (frdA, osmA) nitrogen metabolism (niaD, niiA) and respiration (rcfB). We show that the NO-detoxifying flavohemoprotein fhpA is strongly induced by hypoxia independent of the nitrogen source, but is dispensable for hypoxic survival. By deleting the nitrate reductase gene niaD, the nitrite reductase gene niiA and the two fumarate reductases genes frdA and osmA, we found that alternative electron acceptors such as nitrate and fumarate do not have a significant impact on growth of A. fumigatus during hypoxia, but that functional mitochondrial respiratory chain complexes are essential under these conditions. Inhibition studies indicated that primarily complex III and IV play a crucial role in the hypoxic growth of A. fumigatus.

ORGANISM(S): Aspergillus fumigatus

SUBMITTER: Wolfgang Schmidt-Heck

PROVIDER: E-MTAB-2699 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:MicroRNAs (miRNAs) are a class of endogenous, non-coding RNAs that mediate post-transcriptional gene silencing by inhibiting mRNA translation and promoting mRNA decay. DICER1, an RNAse III endonuclease encoded by Dicer1, is required for processing short 21-22 nucleotide miRNAs from longer double-stranded RNA precursors. Here, we investigate the loss of Dicer1 in mouse postnatal male germ cells to determine how disruptions in the miRNA biogenesis pathway may contribute to infertility. Reduced levels of Dicer1 transcripts and DICER1 were confirmed in germ cell knock-out (GCKO) testes by postnatal day 18 (P18). Compared to wild-type (WT) at 8 weeks, GCKO males had no change in body weight, yet showed significant reductions in testis mass and sperm number. Histology and fertility tests confirmed spermatogenic failure in GCKO males. Array analyses at P18 showed 96% of miRNA genes were down-regulated and 37% of protein-coding genes were differentially expressed in GCKO testes. Interestingly, we observed preferential overexpression of genes on the sex chromosomes in GCKO testes, with more than 80% of the genes overlapping those proposed to undergo meiotic sex chromosome inactivation (MSCI) in the germ cells. Compared to WT, GCKO mice showed higher percentages of cells at early meiotic stages (leptotene and zygotene) but lower percentages at later stages (pachytene, diplotene and metaphase I), providing evidence that deletion of Dicer1 leads to disruptions in meiotic progression. Furthermore, we observed fewer elongating spermatids with proper translational activation of transition protein 2 (Tnp2), protamine 1 and 2 (Prm1 and Prm2) in GCKO testes after step 12-14. Therefore, deleting Dicer1 in early postnatal germ cells causes misregulation of transcripts encoded by genes on the sex chromosomes, impairs meiotic progression and post-meiotic translational control and results in spermatogenic failure and infertility. Total RNA, including miRNAs, were purified from a total of six individual mouse samples. The tissue collected was obtained from wild-type (control; n=3) and Dicer1 germ cell knockout (mutant; n=3) testes on P18. One miRNA GCKO sample, M36, was determined to be of poor quality and was excluded from the study; thus, a total of five miRNA samples were analyzed.

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Long-term adaptation to hypoxic conditions - Febit transcriptome analysis

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