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Replication Initiation from a Novel Origin Identified in the Th2 Cytokine Cluster Locus Requires a Distant Conserved Noncoding Sequence¹

Toshiro Hayashida^*, Masako Oda^2,, Kanako Ohsawa, Atsumi Yamaguchi^*, Takumi Hosozawa^*, Richard M. Locksley, Mauro Giacca, Hisao Masai^3, and Shoichiro Miyatake^3,*

^* Cytokine Project and Genome Dynamics Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Howard Hughes Medical Institute and Department of Medicine, University of California San Francisco, CA 94143; and International Centre for Genetic Engineering and Biotechnology, Trieste, Italy

Lineage commitment of Th cells is associated with the establishment of specific transcriptional programs of cytokines. However, how Th cell differentiation affects the program of DNA replication has not been addressed. To gain insight into interplays between differentiation-induced transcription regulation and initiation of DNA replication, we took advantage of an in vitro differentiation system of naive T cells, in which one can manipulate their differentiation into Th1 or Th2 cells. We searched for replication origins in the murine IL-4/IL-13 locus and compared their profiles in the two Th cell lineages which were derived in vitro from the same precursor T cells. We identified a replication origin (ori_IL-13) downstream from exon 4 of IL-13 and showed that this origin functions in both Th2 and Th1 cells. A distant regulatory element called CNS-1 (conserved noncoding sequence 1) in the IL-4/IL-13 intergenic region coincides with a Th2-specific DNase I-hypersensitive site and is required for efficient, coordinated expression of Th2 cytokines. Replication initiation from ori_IL-13 is significantly reduced in Th1 and Th2 cells derived from CNS-1-deficient mice. However, the replication timing of this locus is consistently early during S phase in both Th1 and Th2 cells under either the wild-type or CNS-1 deletion background. Thus, the conserved noncoding element in the intergenic region regulates replication initiation from a distant replication origin in a manner independent from its effect on lineage-specific transcription but not the replication timing of the segment surrounding this origin.