Walter and Eliza Hall Institute of Medical Research

About: Walter and Eliza Hall Institute of Medical Research is a nonprofit organization based out in Melbourne, Victoria, Australia. It is known for research contribution in the topics: Antigen & Immune system. The organization has 5012 authors who have published 10620 publications receiving 873561 citations.

Regulation of an essential innate immune response by the p50 subunit of NF-kappaB.

Abstract: Recognition of bacterial endotoxin (LPS) elicits multiple host responses, including activation of cells of the innate im- mune system. LPS exposure occurs repeatedly during septi- cemia, making strict regulation of gene expression neces- sary. Such regulation might prevent, for example, the continuous production of proinflammatory cytokines such as tumor necrosis factor (TNF), which could lead to severe vascular collapse. Tolerance to LPS is characterized by a di- minished production of TNF during prolonged exposure to LPS, and is therefore likely to represent an essential control mechanism during sepsis. In the present study, which uses mice with genetic deletions of the proteins of NF- k B com- plex, we provide data demonstrating that increased expres- sion of the p50 subunit of NF- k B directly results in the downregulation of LPS-induced TNF production. This con- tention is supported by the following observations: (1) toler- ance to LPS is not induced in macrophages from p50 2 / 2 mice; (2) long-term pretreatment with LPS does not block synthesis of TNF mRNA in p50 2 / 2 macrophages (in con- trast to wild-type macrophages); (3) ectopic overexpression of p50 reduces transcriptional activation of the murine TNF promoter; and (4) analysis of the four k B sites from the mu- rine TNF promoter demonstrates that binding of p50 ho- modimers to the positively acting k B3 element is associated with development of the LPS-tolerant phenotype. Thus, p50 expression plays a key role in the development of LPS toler- ance. ( J. Clin. Invest. 1998. 102:1645—1652.) Key words: li- popolysaccharide ¥ tumor necrosis factor ¥ macrophages ¥ sepsis ¥ regulation of transcription

Metabonomic, transcriptomic, and genomic variation of a population cohort

Abstract: Comprehensive characterization of human tissues promises novel insights into the biological architecture of human diseases and traits. We assessed metabonomic, transcriptomic, and genomic variation for a large population-based cohort from the capital region of Finland. Network analyses identified a set of highly correlated genes, the lipid‐leukocyte (LL) module, as having a prominent role in over 80 serum metabolites (of 134 measures quantified), including lipoprotein subclasses, lipids, and amino acids. Concurrent association with immune response markers suggested the LL module as a possible link between inflammation, metabolism, and adiposity. Further, genomic variation was used to generate a directed network and infer LL module’s largely reactive nature to metabolites. Finally, gene co-expression in circulating leukocytes was shown to be dependent on serum metabolite concentrations, providing evidence for the hypothesis that the coherence of molecular networks themselves is conditional on environmental factors. These findings show the importance and opportunityof systematic molecular investigation of human population samples.To facilitate and encourage this investigation, the metabonomic, transcriptomic, and genomic data used in this study have been made available as a resource for the research community. Molecular Systems Biology 6: 441; published online 21 December 2010; doi:10.1038/msb.2010.93 Subject Categories: functional genomics; metabolic and regulatory networks

Meiotic and epigenetic defects in Dnmt3L-knockout mouse spermatogenesis

Abstract: The production of mature germ cells capable of generating totipotent zygotes is a highly specialized and sexually dimorphic process. The transition from diploid primordial germ cell to haploid spermatozoa requires genome-wide reprogramming of DNA methylation, stage- and testis-specific gene expression, mitotic and meiotic division, and the histone-protamine transition, all requiring unique epigenetic control. Dnmt3L, a DNA methyltransferase regulator, is expressed during gametogenesis, and its deletion results in sterility. We found that during spermatogenesis, Dnmt3L contributes to the acquisition of DNA methylation at paternally imprinted regions, unique nonpericentric heterochromatic sequences, and interspersed repeats, including autonomous transposable elements. We observed retrotransposition of an LTR-ERV1 element in the DNA from Dnmt3L-/- germ cells, presumably as a result of hypomethylation. Later in development, in Dnmt3L-/- meiotic spermatocytes, we detected abnormalities in the status of biochemical markers of heterochromatin, implying aberrant chromatin packaging. Coincidentally, homologous chromosomes fail to align and form synaptonemal complexes, spermatogenesis arrests, and spermatocytes are lost by apoptosis and sloughing. Because Dnmt3L expression is restricted to gonocytes, the presence of defects in later stages reveals a mechanism whereby early genome reprogramming is linked inextricably to changes in chromatin structure required for completion of spermatogenesis.