Science

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Now showing 1 - 6 of 6
  • (2012) Funnell, Alister; Norton, Laura; Mak, Ka Sin; Burdach, John; Artuz, Crisbel; Twine, Natalie; Wilkins, Marc; Hung, TT; Perdomo, Jose; Power, Carl; Koh, P; Bell Anderson, Kim; Orkin, S; Fraser, Stuart; Perkins, Andrew; Pearson, Richard; Crossley, Merlin
    Journal Article
    The CACCC-box binding protein erythroid Krüppel-like factor (EKLF/KLF1) is a master regulator that directs the expression of many important erythroid genes. We have previously shown that EKLF drives transcription of the gene for a second KLF, basic Krüppel-like factor, or KLF3. We have now tested the in vivo role of KLF3 in erythroid cells by examining Klf3 knockout mice. KLF3-deficient adults exhibit a mild compensated anemia, including enlarged spleens, increased red pulp, and a higher percentage of erythroid progenitors, together with elevated reticulocytes and abnormal erythrocytes in the peripheral blood. Impaired erythroid maturation is also observed in the fetal liver. We have found that KLF3 levels rise as erythroid cells mature to become TER119(+). Consistent with this, microarray analysis of both TER119(-) and TER119(+) erythroid populations revealed that KLF3 is most critical at the later stages of erythroid maturation and is indeed primarily a transcriptional repressor. Notably, many of the genes repressed by KLF3 are also known to be activated by EKLF. However, the majority of these are not currently recognized as erythroid-cell-specific genes. These results reveal the molecular and physiological function of KLF3, defining it as a feedback repressor that counters the activity of EKLF at selected target genes to achieve normal erythropoiesis.

  • (2013) Funnell, Alister; Mak, Ka Sin; Twine, Natalie; Pelka, G; Norton, Laura; Radziewic, T; Power, M; Wilkins, Marc; Bell Anderson, Kim; Fraser, Stuart; Perkins, Andrew; Tam, P; Pearson, Richard; Crossley, Merlin
    Journal Article
    Krüppel-like factors 3 and 8 (KLF3 and KLF8) are highly related transcriptional regulators that bind to similar sequences of DNA. We have previously shown that in erythroid cells there is a regulatory hierarchy within the KLF family, whereby KLF1 drives the expression of both the Klf3 and Klf8 genes and KLF3 in turn represses Klf8 expression. While the erythroid roles of KLF1 and KLF3 have been explored, the contribution of KLF8 to this regulatory network has been unknown. To investigate this, we have generated a mouse model with disrupted KLF8 expression. While these mice are viable, albeit with a reduced life span, mice lacking both KLF3 and KLF8 die at around embryonic day 14.5 (E14.5), indicative of a genetic interaction between these two factors. In the fetal liver, Klf3 Klf8 double mutant embryos exhibit greater dysregulation of gene expression than either of the two single mutants. In particular, we observe derepression of embryonic, but not adult, globin expression. Taken together, these results suggest that KLF3 and KLF8 have overlapping roles in vivo and participate in the silencing of embryonic globin expression during development.

  • (2013) Bell Anderson, Kim; Funnell, Alister; Williams, Helen; Mat Jusoh, H; Scully, T; Lim, Wooi; Burdach, John; Mak, Ka Sin; Knights, Alexander; Hoy, A; Nicholas, Hannah; Sainsbury, A; Turner, N; Pearson, Richard; Crossley, Merlin
    Journal Article
    Krüppel-like factor 3 (KLF3) is a transcriptional regulator that we have shown to be involved in the regulation of adipogenesis in vitro. Here, we report that KLF3-null mice are lean and protected from diet-induced obesity and glucose intolerance. On a chow diet, plasma levels of leptin are decreased, and adiponectin is increased. Despite significant reductions in body weight and adiposity, wild-type and knockout animals show equivalent energy intake, expenditure, and excretion. To investigate the molecular events underlying these observations, we used microarray analysis to compare gene expression in Klf3(+/+) and Klf3(-/-) tissues. We found that mRNA expression of Fam132a, which encodes a newly identified insulin-sensitizing adipokine, adipolin, is significantly upregulated in the absence of KLF3. We confirmed that KLF3 binds the Fam132a promoter in vitro and in vivo and that this leads to repression of promoter activity. Further, plasma adipolin levels were significantly increased in Klf3(-/-) mice compared with wild-type littermates. Boosting levels of adipolin via targeting of KLF3 offers a novel potential therapeutic strategy for the treatment of insulin resistance.

  • (2013) Wilkins, David; van Sebille, Erik; Rintoul, S; Lauro, Federico M; Cavicchioli, Ricardo
    Journal Article
    Although environmental selection and spatial separation have been shown to shape the distribution and abundance of marine microorganisms, the effects of advection (physical transport) have not been directly tested. Here we examine 25 samples covering all major water masses of the Southern Ocean to determine the effects of advection on microbial biogeography. Even when environmental factors and spatial separation are controlled for, there is a positive correlation between advection distance and taxonomic dissimilarity, indicating that an 'advection effect' has a role in shaping marine microbial community composition. This effect is likely due to the advection of cells increasing the probability that upstream microorganisms will colonize downstream sites. Our study shows that in addition to distance and environmental selection, advection shapes the composition of marine microbial communities.

  • (2013) Kavanagh, Tomas; Mills, James D; Kim, Woojin S; Halliday, Glenda; Janitz, Michael
    Journal Article
    Pathway analysis is a powerful method for discerning differentially regulated genes and elucidating their biological importance. It allows for the identification of perturbed or aberrantly expressed genes within a biological context from extensive data sets and offers a simplistic approach for interrogating such datasets. With the growing use of microarrays and RNA-Seq data for genome wide studies is growing at an alarming rate and the use of deep sequencing is revealing elements of the genome previously uncharacterised. Through the employment of pathway analysis, mechanisms in complex diseases may be explored, and novel causatives found primarily through differentially regulated genes. Further, with the implementation of next generation sequencing (NGS) a deeper resolution may be attained, particularly in identification of isoform diversity and SNP’s. Here we look at a broad overview of pathway analysis in the human brain transcriptome and its relevance in teasing out underlying causes of complex diseases. We will outline processes in data gathering and analysis of particular diseases in which these approaches have been successful.

  • (2012) Wong, Jenny; Garner, Brett; Halliday, Glenda; Sharpe, Laura J; Brown, Andrew J
    Journal Article
    Selective Alzheimer’s Disease Indicator-1 (Seladin-1) was originally identified by its down-regulation in the brains of Alzheimer’s Disease (AD) patients. Here, we re-examine existing data and present new gene expression data that refutes its role as a selective AD indicator. Furthermore, we caution against the use of the name “Seladin-1” and instead recommend adoption of the approved nomenclature, 3â-hydroxysterol Ä24-reductase (or DHCR24), which describes its catalytic function in cholesterol synthesis. Further work is required to determine what link, if any, exists between DHCR24 and AD.