Reprogramming of lysosomal gene expression by interleukin-4 and Stat6
File(s)
Author(s)
Type
Journal Article
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.
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.
Date Issued
2013-12-05
Date Acceptance
2013-11-26
Citation
BMC Genomics, 2013, 14
ISSN
1471-2164
Publisher
BioMed Central
Journal / Book Title
BMC Genomics
Volume
14
Copyright Statement
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
License URL
Sponsor
Asthma UK
Commission of the European Communities
Medical Research Council (MRC)
Grant Number
06/050
233015
G1000758
Subjects
Science & Technology
Life Sciences & Biomedicine
Biotechnology & Applied Microbiology
Genetics & Heredity
BIOTECHNOLOGY & APPLIED MICROBIOLOGY
GENETICS & HEREDITY
TRANSCRIPTION FACTOR
C57BL/6J MICE
MITOCHONDRIAL BIOGENESIS
ALTERNATIVE ACTIVATION
CYSTEINE CATHEPSINS
CELLULAR CLEARANCE
MODULE NETWORKS
SMALL-INTESTINE
RECEPTOR-ALPHA
BINDING-SITES
Animals
Cells, Cultured
Cluster Analysis
Gene Expression Regulation
Gene Regulatory Networks
Interleukin-4
Lysosomes
Macrophages
Male
Mice
Mice, Inbred C57BL
Oligonucleotide Array Sequence Analysis
STAT6 Transcription Factor
Bioinformatics
06 Biological Sciences
11 Medical And Health Sciences
08 Information And Computing Sciences
Publication Status
Published
Article Number
853