Global Regulation of Promoter Melting in Naive Lymphocytes

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• 作者：Fedor Kouzine¹ ; ⁹ ; Damian Wojtowicz² ; ⁶ ; ⁹ ; Arito Yamane³ ; ⁹ ; ¹⁰ ; Wolfgang Resch³ ; Kyong-Rim Kieffer-Kwon³ ; Russell Bandle¹ ; Steevenson Nelson³ ; Hirotaka Nakahashi³ ; Parirokh Awasthi⁵ ; Lionel Feigenbaum⁵ ; Herve Menoni⁷ ; Jan Hoeijmakers⁷ ; Wim Vermeulen⁷ ; Hui Ge⁸ ; Teresa M. Przytycka² ; ⁹ ; David Levens¹ ; ⁹ ; ^{levens@helix.nih.gov} ; Rafael Casellas³ ; ⁴ ; ⁹ ; ^{casellar@mail.nih.gov}
• 刊名：Cell
• 出版年：2013
• 出版时间：23 May, 2013
• 年：2013
• 卷：153
• 期：5
• 页码：988-999
• 全文大小：2477 K

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Summary

Lymphocyte activation is initiated by a global increase in messenger RNA synthesis. However, the mechanisms driving transcriptome amplification during the immune response are unknown. By monitoring single-stranded DNA genome wide, we show that the genome of naive cells is poised for rapid activation. In G₀, ¡«90 % of promoters from genes to be expressed in cycling lymphocytes are polymerase loaded but unmelted and support only basal transcription. Furthermore, the transition from abortive to productive elongation is kinetically limiting, causing polymerases to accumulate nearer to transcription start sites. Resting lymphocytes also limit the expression of the transcription factor IIH complex, including XPB and XPD helicases involved in promoter melting and open complex extension. To date, two rate-limiting steps have been shown to control global gene expression in eukaryotes: preinitiation complex assembly and polymerase pausing. Our studies identify promoter melting as a third key regulatory step and propose that this mechanism ensures a prompt lymphocyte response to invading pathogens.