title: Global regulation of promoter melting in naive lymphocytes.
abstract: 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.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Fedor
authors.initials: F
authors.lastname: Kouzine
authors.forename: Damian
authors.initials: D
authors.lastname: Wojtowicz
authors.forename: Arito
authors.initials: A
authors.lastname: Yamane
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Resch
authors.forename: Kyong-Rim
authors.initials: KR
authors.lastname: Kieffer-Kwon
authors.forename: Russell
authors.initials: R
authors.lastname: Bandle
authors.forename: Steevenson
authors.initials: S
authors.lastname: Nelson
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Nakahashi
authors.forename: Parirokh
authors.initials: P
authors.lastname: Awasthi
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Herve
authors.initials: H
authors.lastname: Menoni
authors.forename: Jan
authors.initials: J
authors.lastname: Hoeijmakers
authors.forename: Wim
authors.initials: W
authors.lastname: Vermeulen
authors.forename: Hui
authors.initials: H
authors.lastname: Ge
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Przytycka
authors.forename: David
authors.initials: D
authors.lastname: Levens
authors.forename: Rafael
authors.initials: R
authors.lastname: Casellas
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D004277:DNA, Single-Stranded / Q000378:metabolism; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic; D051758:Transcription Factor TFIIH / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D004277:DNA, Single-Stranded; D051758:Transcription Factor TFIIH