TY - JOUR
T1 - XGlobal regulation of promoter melting in naive lymphocytes
AU - Kouzine, Fedor
AU - Wojtowicz, Damian
AU - Yamane, Arito
AU - Resch, Wolfgang
AU - Kieffer-Kwon, Kyong Rim
AU - Bandle, Russell
AU - Nelson, Steevenson
AU - Nakahashi, Hirotaka
AU - Awasthi, Parirokh
AU - Feigenbaum, Lionel
AU - Menoni, Herve
AU - Hoeijmakers, Jan
AU - Vermeulen, Wim
AU - Ge, Hui
AU - Przytycka, Teresa M.
AU - Levens, David
AU - Casellas, Rafael
N1 - Funding Information:
We thank G. Gutierrez for technical assistance with the genome analyzer; J. Simone and J. Lay for bone marrow sorts; J. Qian and K. Zaal for the B cell confocal micrographs; and C. Benham for SIDD mapping. We thank the Casellas and Levens lab members for critically reading the manuscript. We also thank A. Hoofring from the National Institutes of Health (NIH) Medical Arts for designing the pictures shown in Figure 6D. This work was supported in part by the Intramural Research Program of National Institute of Arthritis and Musculoskeletal and Skin Diseases (NAIMS), the National Cancer Institute (Center for Cancer Research), and the National Library of Medicine of the NIH. This study utilized the high-performance computational capabilities of the Helix Systems at the NIH ( http://helix.nih.gov ). All animal experiments were performed according to the NIH guidelines for laboratory animals and were approved by the Scientific Committee of the NIAMS Animal Facilities. For questions regarding computational analysis, please contact T.M.P. ( [email protected] ).
PY - 2013/5/23
Y1 - 2013/5/23
N2 - 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 G 0, ∼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.
AB - 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 G 0, ∼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.
UR - https://www.scopus.com/pages/publications/84878315605
U2 - 10.1016/j.cell.2013.04.033
DO - 10.1016/j.cell.2013.04.033
M3 - Article
C2 - 23706737
AN - SCOPUS:84878315605
SN - 0092-8674
VL - 153
SP - 988
JO - Cell
JF - Cell
IS - 5
ER -