Chromosome Transfer Activates and Delineates a Locus Control Region for Perforin

Matthew E. Pipkin; Belma Ljutic; Fernando Cruz-Guilloty; Marcela Nouzova; Anjana Rao; Juan Carlos Zúñiga-Pflücker; Mathias G. Lichtenheld

doi:10.1016/j.immuni.2006.11.009

Chromosome Transfer Activates and Delineates a Locus Control Region for Perforin

Matthew E. Pipkin, Belma Ljutic, Fernando Cruz-Guilloty, Marcela Nouzova, Anjana Rao, Juan Carlos Zúñiga-Pflücker, Mathias G. Lichtenheld

Microbiology & Immunology

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

Perforin gene (PRF1) transcription regulates perforin expression in NK cells and CTL. Here we identified the locus-wide ensemble of cis-acting sequences that drives PRF1 transcription physiologically. By using chromosome transfer, we revealed that de novo activation of a silent PRF1 locus was controlled by a 150 kb domain comprised of 16 DNase I hypersensitive sites (DHSs). These cis-acting sequences included a locus control region (LCR) and conferred developmentally appropriate and lineage-specific expression of human perforin from BAC transgenes. The LCR included four distal DHSs that were required for perforin expression from its natural locus, and their engineered deletion from the PRF1 BAC transgene abolished LCR function and led to rapid gene silencing. Thus, LCR function is central for regulating the developmental and activation-specific PRF1 promoter activity characteristic of NK cells and CTL.

Original language	English (US)
Pages (from-to)	29-41
Number of pages	13
Journal	Immunity
Volume	26
Issue number	1
DOIs	https://doi.org/10.1016/j.immuni.2006.11.009
State	Published - Jan 2007

Keywords

DNA
MOLIMMUNO

ASJC Scopus subject areas

Immunology and Allergy
Infectious Diseases
Immunology

UN SDGs

This output contributes to the following Sustainable Development Goal(s)

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10.1016/j.immuni.2006.11.009

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title = "Chromosome Transfer Activates and Delineates a Locus Control Region for Perforin",

abstract = "Perforin gene (PRF1) transcription regulates perforin expression in NK cells and CTL. Here we identified the locus-wide ensemble of cis-acting sequences that drives PRF1 transcription physiologically. By using chromosome transfer, we revealed that de novo activation of a silent PRF1 locus was controlled by a 150 kb domain comprised of 16 DNase I hypersensitive sites (DHSs). These cis-acting sequences included a locus control region (LCR) and conferred developmentally appropriate and lineage-specific expression of human perforin from BAC transgenes. The LCR included four distal DHSs that were required for perforin expression from its natural locus, and their engineered deletion from the PRF1 BAC transgene abolished LCR function and led to rapid gene silencing. Thus, LCR function is central for regulating the developmental and activation-specific PRF1 promoter activity characteristic of NK cells and CTL.",

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author = "Pipkin, {Matthew E.} and Belma Ljutic and Fernando Cruz-Guilloty and Marcela Nouzova and Anjana Rao and Z{\'u}{\~n}iga-Pfl{\"u}cker, {Juan Carlos} and Lichtenheld, {Mathias G.}",

note = "Funding Information: We would like to thank L.H. Boise, S. Monticelli, and H. Hu for their review of the manuscript. We are grateful to A. Benigno and R. Donahue (Dr. John T. Macdonald Foundation Center for Medical Genetics, University of Miami) for their expertise in FISH analysis, D. Kolonias for providing primary T cells (Tissue and Blood Banking Facility, University of Miami), G. Munson (Department of Microbiology and Immunology, University of Miami) for advice and tools for site-specific recombination, and M. Perez for assistance in manuscript preparation. This work was supported by a grant from the Sylvester Comprehensive Cancer Center to M.G.L. and by NIH grant AI 44432 to A.R. J.C.Z.-P. is supported by a Canada Research Chair in Developmental Immunology and by funds from the Canadian Cancer Society. ",

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AU - Pipkin, Matthew E.

AU - Ljutic, Belma

AU - Cruz-Guilloty, Fernando

AU - Nouzova, Marcela

AU - Rao, Anjana

AU - Zúñiga-Pflücker, Juan Carlos

AU - Lichtenheld, Mathias G.

N1 - Funding Information: We would like to thank L.H. Boise, S. Monticelli, and H. Hu for their review of the manuscript. We are grateful to A. Benigno and R. Donahue (Dr. John T. Macdonald Foundation Center for Medical Genetics, University of Miami) for their expertise in FISH analysis, D. Kolonias for providing primary T cells (Tissue and Blood Banking Facility, University of Miami), G. Munson (Department of Microbiology and Immunology, University of Miami) for advice and tools for site-specific recombination, and M. Perez for assistance in manuscript preparation. This work was supported by a grant from the Sylvester Comprehensive Cancer Center to M.G.L. and by NIH grant AI 44432 to A.R. J.C.Z.-P. is supported by a Canada Research Chair in Developmental Immunology and by funds from the Canadian Cancer Society.

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N2 - Perforin gene (PRF1) transcription regulates perforin expression in NK cells and CTL. Here we identified the locus-wide ensemble of cis-acting sequences that drives PRF1 transcription physiologically. By using chromosome transfer, we revealed that de novo activation of a silent PRF1 locus was controlled by a 150 kb domain comprised of 16 DNase I hypersensitive sites (DHSs). These cis-acting sequences included a locus control region (LCR) and conferred developmentally appropriate and lineage-specific expression of human perforin from BAC transgenes. The LCR included four distal DHSs that were required for perforin expression from its natural locus, and their engineered deletion from the PRF1 BAC transgene abolished LCR function and led to rapid gene silencing. Thus, LCR function is central for regulating the developmental and activation-specific PRF1 promoter activity characteristic of NK cells and CTL.

AB - Perforin gene (PRF1) transcription regulates perforin expression in NK cells and CTL. Here we identified the locus-wide ensemble of cis-acting sequences that drives PRF1 transcription physiologically. By using chromosome transfer, we revealed that de novo activation of a silent PRF1 locus was controlled by a 150 kb domain comprised of 16 DNase I hypersensitive sites (DHSs). These cis-acting sequences included a locus control region (LCR) and conferred developmentally appropriate and lineage-specific expression of human perforin from BAC transgenes. The LCR included four distal DHSs that were required for perforin expression from its natural locus, and their engineered deletion from the PRF1 BAC transgene abolished LCR function and led to rapid gene silencing. Thus, LCR function is central for regulating the developmental and activation-specific PRF1 promoter activity characteristic of NK cells and CTL.

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Chromosome Transfer Activates and Delineates a Locus Control Region for Perforin

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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