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Transcription Elongation Factor S-II Is Required for Definitive Hematopoiesis

Takahiro Ito,^1, Nagisa Arimitsu,^1, Masaki Takeuchi,^2, Nobuyuki Kawamura,¹ Makiko Nagata,¹ Kayoko Saso,¹ Nobuyoshi Akimitsu,¹ Hiroshi Hamamoto,¹ Shunji Natori,¹ Atsushi Miyajima,² and Kazuhisa Sekimizu^1*

Division of Developmental Biochemistry, Graduate School of Pharmaceutical Sciences,¹ Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo, Tokyo 113-0033, Japan²

Received 20 December 2005/ Accepted 27 January 2006

Transcription elongation factor S-II/TFIIS promotes readthrough of transcriptional blocks by stimulating nascent RNA cleavage activity of RNA polymerase II in vitro. The biologic significance of S-II function in higher eukaryotes, however, remains unclear. To determine its role in mammalian development, we generated S-II-deficient mice through targeted gene disruption. Homozygous null mutants died at midgestation with marked pallor, suggesting severe anemia. S-II^–/– embryos had a decreased number of definitive erythrocytes in the peripheral blood and disturbed erythroblast differentiation in fetal liver. There was a dramatic increase in apoptotic cells in S-II^–/– fetal liver, which was consistent with a reduction in Bcl-x_L gene expression. The presence of phenotypically defined hematopoietic stem cells and in vitro colony-forming hematopoietic progenitors in S-II^–/– fetal liver indicates that S-II is dispensable for the generation and differentiation of hematopoietic stem cells. S-II-deficient fetal liver cells, however, exhibited a loss of long-term repopulating potential when transplanted into lethally irradiated adult mice, indicating that S-II deficiency causes an intrinsic defect in the self-renewal of hematopoietic stem cells. Thus, S-II has critical and nonredundant roles in definitive hematopoiesis.

These authors contributed equally to this work.