T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer.
The ribonuclease III enzyme Dicer is essential for the processing of micro-RNAs (miRNAs) and small interfering RNAs (siRNAs) from double-stranded RNA precursors. miRNAs and siRNAs regulate chromatin structure, gene transcription, mRNA stability, and translation in a wide range of organisms. To provide a model system to explore the role of Dicer-generated RNAs in the differentiation of mammalian cells in vivo, we have generated a conditional Dicer allele. Deletion of Dicer at an early stage of T cell development compromised the survival of alphabeta lineage cells, whereas the numbers of gammadelta-expressing thymocytes were not affected. In developing thymocytes, Dicer was not required for the maintenance of transcriptional silencing at pericentromeric satellite sequences (constitutive heterochromatin), the maintenance of DNA methylation and X chromosome inactivation in female cells (facultative heterochromatin), and the stable shutdown of a developmentally regulated gene (developmentally regulated gene silencing). Most remarkably, given that one third of mammalian mRNAs are putative miRNA targets, Dicer seems to be dispensable for CD4/8 lineage commitment, a process in which epigenetic regulation of lineage choice has been well documented. Thus, although Dicer seems to be critical for the development of the early embryo, it may have limited impact on the implementation of some lineage-specific gene expression programs.
Cobb
Bradley S
BS
Lymphocyte Development Group, Medical Research Council Clinical Sciences Centre, Imperial College London, London W12 0NN, England, UK.
Nesterova
Tatyana B
TB
Thompson
Elizabeth
E
Hertweck
Arnulf
A
O'Connor
Eric
E
Godwin
Jonathan
J
Wilson
Christopher B
CB
Brockdorff
Neil
N
Fisher
Amanda G
AG
Smale
Stephen T
ST
Merkenschlager
Matthias
M
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D015139:Blotting, Southern; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D018899:CpG Islands / Q000502:physiology; D019175:DNA Methylation; D018507:Gene Expression Regulation, Developmental; D006570:Heterochromatin / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics*; D013601:T-Lymphocytes / Q000502:physiology*
D006570:Heterochromatin; D043244:Ribonuclease III