title: Reprogramming of lysosomal gene expression by interleukin-4 and Stat6.
abstract: BACKGROUND
  Lysosomes play important roles in multiple aspects of physiology, but the problem of how the transcription of lysosomal genes is coordinated remains incompletely understood. The goal of this study was to illuminate the physiological contexts in which lysosomal genes are coordinately regulated and to identify transcription factors involved in this control.
  
  
  RESULTS
  As transcription factors and their target genes are often co-regulated, we performed meta-analyses of array-based expression data to identify regulators whose mRNA profiles are highly correlated with those of a core set of lysosomal genes. Among the ~50 transcription factors that rank highest by this measure, 65% are involved in differentiation or development, and 22% have been implicated in interferon signaling. The most strongly correlated candidate was Stat6, a factor commonly activated by interleukin-4 (IL-4) or IL-13. Publicly available chromatin immunoprecipitation (ChIP) data from alternatively activated mouse macrophages show that lysosomal genes are overrepresented among Stat6-bound targets. Quantification of RNA from wild-type and Stat6-deficient cells indicates that Stat6 promotes the expression of over 100 lysosomal genes, including hydrolases, subunits of the vacuolar H⁺ ATPase and trafficking factors. While IL-4 inhibits and activates different sets of lysosomal genes, Stat6 mediates only the activating effects of IL-4, by promoting increased expression and by neutralizing undefined inhibitory signals induced by IL-4.
  
  
  CONCLUSIONS
  The current data establish Stat6 as a broadly acting regulator of lysosomal gene expression in mouse macrophages. Other regulators whose expression correlates with lysosomal genes suggest that lysosome function is frequently re-programmed during differentiation, development and interferon signaling.
authors: Louise M
authors: LM
authors: Brignull
authors: Zsolt
authors: Z
authors: Czimmerer
authors: Hafida
authors: H
authors: Saidi
authors: Bence
authors: B
authors: Daniel
authors: Izabel
authors: I
authors: Villela
authors: Nathan W
authors: NW
authors: Bartlett
authors: Sebastian L
authors: SL
authors: Johnston
authors: Lisiane B
authors: LB
authors: Meira
authors: Laszlo
authors: L
authors: Nagy
authors: Division of Biomedical Sciences, Molecular and Metabolic Signaling Centre, St, George's University of London, Cranmer Terrace, London SW17 0RE, UK. a.nohturfft@sgul.ac.uk.
authors: Axel
authors: A
authors: Nohturfft
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016000:Cluster Analysis; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D015847:Interleukin-4 / Q000378:metabolism*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D050800:STAT6 Transcription Factor / Q000378:metabolism*
chemical_list: D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4