A Distal Conserved Sequence Element Controls Ifng Gene Expression by T Cells and NK Cells

Robin D. Hatton; Laurie E. Harrington; Rita J. Luther; Therese Wakefield; Karen M. Janowski; James R. Oliver; Roger L. Lallone; Kenneth M. Murphy; Casey T. Weaver

doi:10.1016/j.immuni.2006.09.007

A Distal Conserved Sequence Element Controls Ifng Gene Expression by T Cells and NK Cells

Robin D. Hatton, Laurie E. Harrington, Rita J. Luther, Therese Wakefield, Karen M. Janowski, James R. Oliver, Roger L. Lallone, Kenneth M. Murphy, Casey T. Weaver

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

153 Scopus citations

Abstract

Chromatin dynamics that regulate Ifng gene expression are incompletely understood. By using cross-species comparative sequence analyses, we have identified conserved noncoding sequences (CNSs) upstream of the Ifng gene, one of which, located -22 kb from the transcriptional start site, contains clustered consensus binding sequences of transcription factors that function in T cell differentiation. CNS-22 was uniquely associated with histone modifications typical of accessible chromatin in both T helper 1 (Th1) and Th2 cells and demonstrated significant and selective T-bet (T-box transcription factor expressed in T cells, Tbx21)-dependent binding and enhancer activity in Th1 cells. Deletion of CNS-22 in the context of an Ifng reporter transgene ablated T cell receptor-dependent and -independent Ifng expression in Th1 effectors and similarly blocked expression by cytotoxic T lymphocytes and natural killer cells. Thus, a single distal element may be essential for Ifng gene expression by both innate and adaptive immune effector cell lineages.

Original language	English
Pages (from-to)	717-729
Number of pages	13
Journal	Immunity
Volume	25
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2006.09.007
State	Published - Nov 2006

Keywords

CELLIMMUNO
DNA

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10.1016/j.immuni.2006.09.007

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title = "A Distal Conserved Sequence Element Controls Ifng Gene Expression by T Cells and NK Cells",

abstract = "Chromatin dynamics that regulate Ifng gene expression are incompletely understood. By using cross-species comparative sequence analyses, we have identified conserved noncoding sequences (CNSs) upstream of the Ifng gene, one of which, located -22 kb from the transcriptional start site, contains clustered consensus binding sequences of transcription factors that function in T cell differentiation. CNS-22 was uniquely associated with histone modifications typical of accessible chromatin in both T helper 1 (Th1) and Th2 cells and demonstrated significant and selective T-bet (T-box transcription factor expressed in T cells, Tbx21)-dependent binding and enhancer activity in Th1 cells. Deletion of CNS-22 in the context of an Ifng reporter transgene ablated T cell receptor-dependent and -independent Ifng expression in Th1 effectors and similarly blocked expression by cytotoxic T lymphocytes and natural killer cells. Thus, a single distal element may be essential for Ifng gene expression by both innate and adaptive immune effector cell lineages.",

keywords = "CELLIMMUNO, DNA",

author = "Hatton, {Robin D.} and Harrington, {Laurie E.} and Luther, {Rita J.} and Therese Wakefield and Janowski, {Karen M.} and Oliver, {James R.} and Lallone, {Roger L.} and Murphy, {Kenneth M.} and Weaver, {Casey T.}",

note = "Funding Information: The authors thank R. Bucy, D. Chaplin, A. Diefenbach, G. Loots, C. Raman, and A. Zajac and members of the Weaver laboratory for their helpful comments and suggestions. We also thank F. Wagner, C. Song, M. Blake, V. Chaplin, and B. Weaver for expert technical assistance. Thanks also to N. LeLievre for outstanding editorial assistance and N. Fineberg for biostatistics support. This work is supported by grants from the NIH (AI035783 and DK64400 to C.T.W., AR049293 to R.D.H., and HL07553 to R.J.L.), Sankyo Co. Ltd (C.T.W.), Howard Hughes Medical Institute (K.M.M.), Crohn's and Colitis Foundation (R.D.H), and a postdoctoral fellowship from the National Multiple Sclerosis Society (L.E.H.). ",

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doi = "10.1016/j.immuni.2006.09.007",

language = "English",

volume = "25",

pages = "717--729",

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T1 - A Distal Conserved Sequence Element Controls Ifng Gene Expression by T Cells and NK Cells

AU - Hatton, Robin D.

AU - Harrington, Laurie E.

AU - Luther, Rita J.

AU - Wakefield, Therese

AU - Janowski, Karen M.

AU - Oliver, James R.

AU - Lallone, Roger L.

AU - Murphy, Kenneth M.

AU - Weaver, Casey T.

N1 - Funding Information: The authors thank R. Bucy, D. Chaplin, A. Diefenbach, G. Loots, C. Raman, and A. Zajac and members of the Weaver laboratory for their helpful comments and suggestions. We also thank F. Wagner, C. Song, M. Blake, V. Chaplin, and B. Weaver for expert technical assistance. Thanks also to N. LeLievre for outstanding editorial assistance and N. Fineberg for biostatistics support. This work is supported by grants from the NIH (AI035783 and DK64400 to C.T.W., AR049293 to R.D.H., and HL07553 to R.J.L.), Sankyo Co. Ltd (C.T.W.), Howard Hughes Medical Institute (K.M.M.), Crohn's and Colitis Foundation (R.D.H), and a postdoctoral fellowship from the National Multiple Sclerosis Society (L.E.H.).

PY - 2006/11

Y1 - 2006/11

N2 - Chromatin dynamics that regulate Ifng gene expression are incompletely understood. By using cross-species comparative sequence analyses, we have identified conserved noncoding sequences (CNSs) upstream of the Ifng gene, one of which, located -22 kb from the transcriptional start site, contains clustered consensus binding sequences of transcription factors that function in T cell differentiation. CNS-22 was uniquely associated with histone modifications typical of accessible chromatin in both T helper 1 (Th1) and Th2 cells and demonstrated significant and selective T-bet (T-box transcription factor expressed in T cells, Tbx21)-dependent binding and enhancer activity in Th1 cells. Deletion of CNS-22 in the context of an Ifng reporter transgene ablated T cell receptor-dependent and -independent Ifng expression in Th1 effectors and similarly blocked expression by cytotoxic T lymphocytes and natural killer cells. Thus, a single distal element may be essential for Ifng gene expression by both innate and adaptive immune effector cell lineages.

AB - Chromatin dynamics that regulate Ifng gene expression are incompletely understood. By using cross-species comparative sequence analyses, we have identified conserved noncoding sequences (CNSs) upstream of the Ifng gene, one of which, located -22 kb from the transcriptional start site, contains clustered consensus binding sequences of transcription factors that function in T cell differentiation. CNS-22 was uniquely associated with histone modifications typical of accessible chromatin in both T helper 1 (Th1) and Th2 cells and demonstrated significant and selective T-bet (T-box transcription factor expressed in T cells, Tbx21)-dependent binding and enhancer activity in Th1 cells. Deletion of CNS-22 in the context of an Ifng reporter transgene ablated T cell receptor-dependent and -independent Ifng expression in Th1 effectors and similarly blocked expression by cytotoxic T lymphocytes and natural killer cells. Thus, a single distal element may be essential for Ifng gene expression by both innate and adaptive immune effector cell lineages.

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SN - 1074-7613

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SP - 717

EP - 729

JO - Immunity

JF - Immunity

IS - 5

ER -

A Distal Conserved Sequence Element Controls Ifng Gene Expression by T Cells and NK Cells

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