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The CACCC-binding protein KLF3/BKLF represses a subset of KLF1/EKLF target genes and is required for proper erythroid maturation in vivo.(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, MerlinJournal ArticleThe 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) Kavanagh, Tomas; Mills, James D; Kim, Woojin S; Halliday, Glenda; Janitz, MichaelJournal ArticlePathway 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 JJournal ArticleSelective 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.