The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fields, P. E.
Right arrow Articles by Flavell, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fields, P. E.
Right arrow Articles by Flavell, R. A.
The Journal of Immunology, 2002, 169: 647-650.
Copyright © 2002 by The American Association of Immunologists

Cutting Edge

Cutting Edge: Changes in Histone Acetylation at the IL-4 and IFN-{gamma} Loci Accompany Th1/Th2 Differentiation

Patrick E. Fields*, Sean T. Kim* and Richard A. Flavell1,*,{dagger}

* Section of Immunobiology, Yale University School of Medicine, and {dagger} Howard Hughes Medical Institute, New Haven, CT 06520


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Peripheral T cell differentiation is accompanied by chromatin changes at the signature cytokine loci. Using chromatin immunoprecipitation we demonstrate that profound increases in histone acetylation occur at the IFN-{gamma} and IL-4 loci during Th1/Th2 differentiation. These changes in histone acetylation status are locus and lineage specific, and are maintained by the transcription factors Tbet and GATA3 in a STAT-dependent manner. Our results suggest a model of cytokine locus activation in which TCR signals initiate chromatin remodeling and locus opening in a cytokine-independent fashion. Subsequently, cytokine signaling reinforces polarization by expanding and maintaining the accessible state at the relevant cytokine locus (IL-4 or IFN-{gamma}). In this model, GATA3 and Tbet serve as transcriptional maintenance factors, which keep the locus accessible to the transcriptional machinery.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Much recent work has focused on the programs of differentiation leading to the development and stability of the Th1 and Th2 phenotypes (1). Lineage commitment by T cells is directed by the cytokine environment in which the T cell encounters Ag. IL-12 and IL-4 can strongly drive differentiation of Th1 and Th2 cells, respectively, via STAT4 and STAT6 (2, 3). GATA3, expressed predominantly in Th2 cells, is critical for Th2 lineage development and may be the principal mediator of STAT6 function (4, 5, 6). Tbet is expressed predominantly in Th1 cells and influences IFN-{gamma} production and Th1 development (7). GATA3 and Tbet may be "master regulators" of Th lineage determination. Both act as transactivators, can induce DNase I hypersensitivity changes in the cytokine loci, and possess negative regulatory functions; GATA3 inhibits IFN-{gamma} expression, and Tbet inhibits Th2 cytokine expression (7, 8, 9, 10).

Epigenetic events are important determinants of cytokine gene expression and lineage commitment. Selective changes in DNase I hypersensitivity and methylation in the IL-4 and IFN-{gamma} loci accompany Th differentiation (11, 12). Also, repositioning of the IL-4 or IFN-{gamma} loci to areas of silencing within the nucleus occurs during Th1 or Th2 differentiation, respectively (13). A causative relationship between chromatin remodeling and Th cell differentiation has not yet been established. The study of other events more closely tied to transcriptional regulation, such as enzymatic modification of histone proteins, might aid in our understanding of such a relationship.

Histones undergo an array of posttranslational modifications on tail domains, including acetylation, phosphorylation, and methylation (14). These modifications, as well as the primary sequence of the histone tails themselves, are highly conserved from yeast to man and have been closely linked to biological events (e.g., replication, transcription, and silencing). High levels of histone acetylation at particular loci correlate with transcriptional activity (15), whereas reduced levels correlate with silencing (16). Factors mediating acetylation and deacetylation serve as transcriptional coactivators and corepressors, respectively, suggesting a causative relationship between acetylation and transcription (17, 18).

We show that histones in the cytokine loci of naive T cells are unacetylated. Upon TCR stimulation, the loci are rapidly and progressively acetylated on histones H3 and H4. Early acetylation occurs in the IL-4 locus irrespective of polarizing conditions, correlating with early transcription. The maintenance of acetylation depends on cytokine/STAT signaling. Tbet and GATA3 also contribute to the polarized acetylated state.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice

Four- to 8-wk-old C57BL/6J, BALB/c, STAT6-/-, and STAT4-/- mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and maintained in the Yale University Animal Resources Center (New Haven, CT).

In vitro T cell differentiation

Naive CD62LhighCD44lowCD4+ T cells were purified by flow cytometric cell (FACS) sorting as previously described (19). These cells were either used directly in chromatin immunoprecipitation (ChIP2; naive samples) or stimulated in 24-well plates under polarizing conditions as described with 1 µg/ml anti-CD3 mAb (145-2C11; American Type Culture Collection, Manassas, VA) plus 1 µg/ml anti-CD28 (37.5.1; American Type Culture Collection) (19). T cells were expanded under the same conditions as the primary cultures. Cytokines were measured (ELISA) from 2 x 105 T cells restimulated for 24 h by plate-bound anti-CD3 (1 µg/ml) plus anti-CD28 (2 µg/ml).

ChIP

For ChIP analysis, 0.5–1.5 x 107 T cells were fixed with 1% formaldehyde for 10 min at 37°C, washed with PBS, and lysed in ChIP lysis buffer (Upstate Biotechnology, Lake Placid, NY). DNA was sonicated by pulsing three to six times. Anti-acetylated histone H3 or H4 was added (4 µl per immunoprecipitation) and incubated overnight. Protein A-agarose beads (Upstate Biotechnology) were added for 1 h then washed once each with low-salt buffer, high-salt buffer, and LiCl buffer, and twice with TE (buffer ingredients are available in the Upstate Biotechnology catalog). Beads were eluted with 0.1 M NaHCO3 and 1% SDS, and cross-links were reversed at 65°C. DNA was ethanol-precipitated in the presence of 20 µg glycogen. Aliquots of equal volume from each sample were used as input controls.

Polymerase chain reaction

PCR was performed on chromatin samples for 28 cycles under standard reaction conditions. Real-time quantitative PCR was performed using an icycler iQ (Bio-Rad, Hercules, CA). Samples were normalized against standard sheared input DNA. Concentrations were determined using the software provided by the manufacturer.

PCR primer sequences (Keck Oligonucleotide Synthesis Facility, Yale University) were as follows: IL-4P, 5'-ACTCATTTTCCCTTGGTTTCAGC-3' and 5'-GATTTTTGTCGCATCCGTGG-3'; IFN-{gamma}P, 5'-CGTAATCCCGAGGAGCCTTC-3' and 5'-CTTTCAATGACTGTGCCGTGG-3'; intronic enhancer (IE), 5'-TCTGCTTGGACATCTCTCTTCCC and 5'-ACCACCCCACAGGTCTTTGTTC-3'; hypersensitive site (HSS), 5'-TTGGGGACAGAGGATGCCTTAC-3' and 5'-GCCTTGCTGAGAGTTTCTTTTGC-3'; TCR{alpha} enhancer, 5'-AGATAGTGAATCAATAGCCAG-3' and 5'-TTCAAAGGGGGACCTGTTT-3'.

Real-time PCR sequences were as follows: IL-4P, 5'-TCTTGATAAACTTAATTGTCTCTCGTCAC-3' and 5'-GCAGGATGACAACTAGCTGGG-3'; IFN-{gamma}P, 5'-TCAGCTGATCCTTTGGACCC-3' and 5'-CTCAGAGCTAGGCCGCAGG-3'.

Fluorogenic probes (Biosearch Technologies, Novato, CA) were as follows: IL-4P, 5'-ACGGGACAGAGCTATTGATGGGTCTCA-3'; IFN-{gamma}P, 5'-CTGACTTGAGACAGAAGTTCTGGGCTTCTCC-3'.

Retroviral transduction

Retroviral transduction of T cells was performed as described (20). Retroviral vectors (K. Murphy, Washington University, St. Louis, MO, and L. Glimcher, Harvard University, Boston, MA), allowed expression of GATA3 or Tbet plus enhanced green fluorescent protein (eGFP) (7, 21). At 24 h after stimulation, cells were infected with retroviral supernatant. At days 5–6, cells were sorted into eGFP-negative and eGFP-positive populations, expanded for 4 days, and either restimulated or used in ChIP experiments. The Phoenix-ECO packaging cell line was a gift of Dr. G. Nolan (Stanford University, Palo Alto, CA).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Histone acetylation in the IL-4 and IFN-{gamma} loci in naive and effector Th cells was assessed using ChIP with Abs specific for acetylated histones H3 or H4. We analyzed the IL-4 and IFN-{gamma} promoter regions (IL-4P and IFN-{gamma}P) as well as two IL-4 locus regulatory regions, the DNase I HSS (CNS-1) and the IE (HS2) (11, 22). These regions coordinately function as enhancers in the IL-4 locus (19, 23). In naive cells, low levels of IL-4P, IFN-{gamma}P, HSS, or IE were coimmunoprecipitated with acetylated histones H3 or H4. In contrast, both H3 and H4 acetylation were substantially greater in day 6 Th1 and Th2 effectors (Fig. 1Go, A and B). In Th1 cells, IFN-{gamma}P, but not the IL-4 locus, was hyperacetylated. Conversely, in Th2 cells, the IL-4 regulatory regions were hyperacetylated, whereas IFN-{gamma}P was not. These acetylation changes persisted in cells rested for 14 days, conditions where no cytokine transcription occurred (data not shown). Acetylation changes appeared to affect the entire IL-4 locus, because identical patterns were observed at distal sites, including the region of the IL-5 gene (data not shown). Input controls demonstrated that equivalent amounts of material were added to each immunoprecipitation (Fig. 1GoC). As an immunoprecipitation control, TCR{alpha} enhancer acetylation was analyzed. Identical results were observed in C57BL/6 (Fig. 1Go), BALB/c (Figs. 2Go and 3Go), and AND TCR-transgenic mice (data not shown), establishing the generality of the findings. Identical patterns of H3 and H4 acetylation suggested that their regulation in the cytokine loci might be similar. Subsequent studies focused on H3 acetylation.



View larger version (99K):
[in this window]
[in a new window]
  		FIGURE 1. Locus- and lineage-specific histone acetylation changes accompany Th differentiation. Histones H3 (A) and H4 (B) acetylation of naive, Th1, and Th2 day 6 effectors. PCR amplification was performed on 5 µl from each 4-fold dilution (starting with undiluted sample). C, Control samples. Shown is a representative of six separate experiments.

 


View larger version (25K):
[in this window]
[in a new window]
  		FIGURE 2. Time course of histone acetylation in the IL-4 and IFN-{gamma} loci. IL-4 (A) or IFN-{gamma} (B) locus acetylation over time. Quantitative, real-time PCR was performed on samples at day 0 (naive cells), or 2, 6, and 12 days after initiation of the cultures. Cells were restimulated at day 6. Relative amounts of DNA in each sample were determined using a standard curve of sonicated DNA of known concentration. Samples were normalized to input DNA. Fold-change from naive samples is plotted. Shown is a representative of three independent experiments.

 


View larger version (38K):
[in this window]
[in a new window]
  		FIGURE 3. Maintenance of histone acetylation in the IL-4 and IFN-{gamma} loci is STAT dependent. Shown is H3 acetylation in wild-type (A), STAT4-/- (B), and STAT6-/- (C) naive, Th1, and Th2 effector T cells. ChIP was performed as described. D, Input controls for wild-type, STAT4-/-, and STAT6-/- cells. E, Time course analysis of H3 acetylation in STAT4-/- (upper panels) and STAT6-/- (lower panels) T cells. At different times after stimulation (as in Fig. 2Go), IL-4P and IFN-{gamma}P H3 acetylation was examined by ChIP. Quantitative PCR was performed as in Fig. 2Go. Shown is a representative of three independent experiments. F, Cytokine production by restimulated wild-type, STAT4-/-, and STAT6-/- T cells. T cells were polarized for 6 days as described. Cells (2 x 105) were restimulated for 48 h with anti-CD3 plus anti-CD28. IL-4 (left panel) and IFN-{gamma} (right panel) were measured in supernatants by ELISA.

 
Kinetics of H3 acetylation was examined by ChIP with quantitative real-time PCR. In Th2-polarized cells, IL-4P acetylation increased at day 2, reaching near-maximum levels by day 6 (Fig. 2GoA). IL-4P acetylation was also observed in Th1-cultured cells at day 2, decreasing by day 6. This observation correlates with early and transient differentiation condition-independent IL-4 transcription (13, 24). Similar patterns at IE and HSS were observed (data not shown). IFN-{gamma}P acetylation patterns resembled those of the IL-4 locus (Fig. 2GoB). Acetylation increases were detectable under both polarizing conditions as early as day 1 (data not shown). Acetylation continued to increase after day 2 in Th1 cultures while decreasing over time in Th2 cultures (Fig. 2GoB). Unlike the IL-4 locus, acetylation at the IFN-{gamma} locus in Th2 cells was substantially less than that in Th1 cells at all time points examined. Early and non-lineage-specific IFN-{gamma} transcription also occurs, but with earlier and more transient kinetics (13). The "window" of acetylation in the IFN-{gamma} locus may be transient and thus was less prominent in these studies. The reduction in acetylation could reflect active deacetylation under opposite polarizing conditions or selection of a population that fails to maintain an acetylated locus. The earliest phase of locus activation occurs independently of cytokine signaling and might be mediated by nonspecific entities triggered by TCR/CD28 stimulation, such as chromatin remodeling complexes (25).

IFN-{gamma}P and IL-4P acetylation was significantly lower in STAT4- and STAT6-deficient T cells cultured under Th1 or Th2 conditions (Fig. 3Go, A–C). Acetylation never reached levels observed in wild-type cells, even after restimulation (Figs. 2Go and 3GoE). Interestingly, IL-4P acetylation was significantly increased in Th1-cultured, STAT4-deficient T cells (Fig. 3Go, B and E). Likewise, IFN-{gamma}P was hyperacetylated in Th2-cultured, STAT6-deficient T cells (Fig. 3Go, C and E). Thus, STAT signaling (i.e., IL-12, IL-4) might negatively affect Th1 or Th2 development by inhibiting cytokine loci accessibility. In the absence of STAT signaling, IL-4 or IFN-{gamma} loci hyperacetylation and transcription proceeded under normally suppressive conditions (Th1 or Th2, respectively). The mechanism by which this cross-regulation occurs is unknown. One possibility is that it is mediated by the coactivators, GATA3 and Tbet, because extinction of their expression is mediated by IL-12 and IL-4, respectively (8, 26). When restimulated, STAT6-deficient T cells cultured under Th2 conditions and STAT4-deficient T cells cultured under Th1 conditions produced detectable amounts of IFN-{gamma} and IL-4, respectively (Fig. 3GoF), consistent with earlier reports (2, 27). These results indicate that the polarizing cytokine milieu can specify cytokine expression in two ways. First, STAT function can maintain cytokine locus accessibility. Second, STATs can inhibit locus accessibility of the opposing cytokine. Whether these putative functions are mediated by direct STAT binding or indirectly by STAT-induced factors remains to be determined.

GATA3 and Tbet are activators of IL-4 and IFN-{gamma} production, respectively. To determine whether these factors affect cytokine locus acetylation, we introduced by retroviral transduction GATA3 or Tbet into STAT6- or STAT4-deficient T cells cultured under Th2 or Th1 conditions, respectively. Transduction of empty virus into STAT6 knockout T cells had no effect on IL-4 locus acetylation (Fig. 4GoA). In contrast, GATA3 significantly enhanced acetylation in the locus (Fig. 4GoA, lower panel). These data correlate with IL-4 transcription in GATA-transduced cells (20, 21). GATA3 induced a slight decrease in acetylation of IFN-{gamma}P (Fig. 4GoA) while also reducing IFN-{gamma} expression (8). Tbet induced a small but reproducible increase (2- to 3-fold) in IFN-{gamma}P acetylation (Fig. 4GoB), consistent with an ability to induce IFN-{gamma} expression (7, 9). In contrast, Tbet did not affect IL-4P acetylation, despite a strong inhibitory effect on IL-4 production (10- to 50-fold; Ref. 7 and data not shown). These results were confirmed by real-time PCR analysis (Fig. 4Go, C and D). Thus, GATA3 and Tbet appear to have a direct effect on acetylation of the IL-4 and IFN-{gamma} loci in the absence of STAT6 and STAT4 signaling. We have not addressed the likely possibility that GATA3 and Tbet might cooperate with other factors, such as NFAT or STATs, to induce optimal IL-4 and IFN-{gamma} locus acetylation and transcription.



View larger version (40K):
[in this window]
[in a new window]
  		FIGURE 4. Changes in histone acetylation at the IL-4 and IFN-{gamma} loci induced by GATA3 and Tbet in STAT-deficient T cells. GATA3 (A) or Tbet (B) were introduced by retroviral transduction into STAT6-/- or STAT4-/- T cells stimulated under Th2 or Th1 conditions, respectively. H3 acetylation of the IL-4 or IFN-{gamma} loci was determined by ChIP on sorted green fluorescent protein (GFP)- and GFP+ populations. Real-time quantitative PCR analysis of GATA3 (C) or Tbet (D) transduced cells was performed as in Fig. 2Go. Relative units were calculated by normalizing the value for each sample to that of the empty vector/GFP-sample.

 
The relationship between acetylation and transcription in these cytokine loci is distinguishable in two ways. First, acetylation is spread over much of the loci, if not the entire loci. This contrasts with acetylation patterns of other gene loci, such as IFN-{beta}, where activation-induced acetylation is restricted to promoter-proximal nucleosomes (28). Second, IL-4 and IFN-{gamma} loci acetylation persists when there is little if any transcription. In contrast, IFN-{beta} locus acetylation occurs during acute stimulation and rapidly dissipates upon loss of the stimulus (28). Thus, acetylation in the IL-4 and IFN-{gamma} loci correlates more closely with transcriptional competence than with acute transcriptional activity, reminiscent of the {beta}-globin locus (15). We postulate that this type of acetylation (widespread and persistent) is a mark of differentiation rather than of transcriptional activation.

Our data support a multistep model of IL-4 and IFN-{gamma} gene activation whereby locus accessibility (as measured by histone acetylation) regulates cytokine expression (29). In the first step, T cell activation results in acetylation (and transcription) of IL-4 and, to a lesser degree, IFN-{gamma}, irrespective of the cytokine environment. This phase is likely mediated by signals generated by TCR/CD28 stimulation. Maintenance and expansion of the accessibility of the relevant cytokine locus, as well as suppressive events preventing the expression of the opposing cytokine, combine to reinforce polarized Th1/Th2 populations. Positive and negative regulation is mediated by STAT proteins as well as GATA3 and Tbet.

Thus, T cell differentiation is characterized by dynamic changes in cytokine locus histone acetylation. Upon initial T cell stimulation, these changes enable early transcription of cytokines, possibly contributing to the cytokine milieu in which T cell differentiation can proceed. Second, they help to establish heritable and stable patterns of cytokine locus accessibility in effector cells, enabling rapid and robust secondary responses. Maintained acetylation would also provide locus and lineage specificity, because transcription factor binding would highly favor an acetylated locus.


   Footnotes
 
1 Address correspondence and reprint requests to Dr. Richard A. Flavell, Yale University School of Medicine and Howard Hughes Medical Institute, 330 Cedar Street, Farnam Medical Building 430, New Haven, CT 06520. E-mail address: Richard.Flavell{at}yale.edu Back

2 Abbreviations used in this paper: ChIP, chromatin immunoprecipitation; GFP, green fluorescent protein; eGFP, enhanced GFP; HSS, hypersensitive site; IE, intronic enhancer. Back

Received for publication March 13, 2002. Accepted for publication May 23, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Murphy, K. M., W. Ouyang, J. D. Farrar, J. Yang, S. Ranganath, H. Asnagli, M. Afkarian, T. L. Murphy. 2000. Signaling and transcription in T helper development. Annu. Rev. Immunol. 18:451.[Medline]
  2. Thierfelder, W. E., J. M. van Deursen, K. Yamamoto, R. A. Tripp, S. R. Sarawar, R. T. Carson, M. Y. Sangster, D. A. Vignali, P. C. Doherty, G. C. Grosveld, J. N. Ihle. 1996. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382:171.[Medline]
  3. Kaplan, M. H., U. Schindler, S. T. Smiley, M. J. Grusby. 1996. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4:313.[Medline]
  4. Zheng, W., R. A. Flavell. 1997. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89:587.[Medline]
  5. Ouyang, W., M. Lohning, Z. Gao, M. Assenmacher, S. Ranganath, A. Radbruch, K. M. Murphy. 2000. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity 12:27.[Medline]
  6. Kurata, H., H. J. Lee, A. O’Garra, N. Arai. 1999. Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells. Immunity 11:677.[Medline]
  7. Szabo, S. J., S. T. Kim, G. L. Costa, X. Zhang, C. G. Fathman, L. H. Glimcher. 2000. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655.[Medline]
  8. Ouyang, W., S. H. Ranganath, K. Weindel, D. Bhattacharya, T. L. Murphy, W. C. Sha, K. M. Murphy. 1998. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity 9:745.[Medline]
  9. Mullen, A. C., F. A. High, A. S. Hutchins, H. W. Lee, A. V. Villarino, D. M. Livingston, A. L. Kung, N. Cereb, T. P. Yao, S. Y. Yang, S. L. Reiner. 2001. Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292:1907.[Abstract/Free Full Text]
  10. Lee, H. J., N. Takemoto, H. Kurata, Y. Kamogawa, S. Miyatake, A. O’Garra, N. Arai. 2000. GATA-3 induces T helper cell type 2 (Th2) cytokine expression and chromatin remodeling in committed Th1 cells. J. Exp. Med. 192:105.[Abstract/Free Full Text]
  11. Agarwal, S., A. Rao. 1998. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9:765.[Medline]
  12. Bird, J. J., D. R. Brown, A. C. Mullen, N. H. Moskowitz, M. A. Mahowald, J. R. Sider, T. F. Gajewski, C. R. Wang, S. L. Reiner. 1998. Helper T cell differentiation is controlled by the cell cycle. Immunity 9:229.[Medline]
  13. Grogan, J. L., M. Mohrs, B. Harmon, D. A. Lacy, J. W. Sedat, R. M. Locksley. 2001. Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity 14:205.
  14. Strahl, B. D., C. D. Allis. 2000. The language of covalent histone modifications. Nature 403:41.[Medline]
  15. Hebbes, T., A. Clayton, A. Thorne, C. Crane-Robinson. 1994. Core histone hyperacetylation co-maps with generalized DNase I sensitivity in the chicken {beta}-globin chromosomal domain. EMBO J. 13:1823.[Medline]
  16. Braunstein, M., A. B. Rose, S. G. Holmes, C. D. Allis, J. R. Broach. 1993. Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 7:592.[Abstract/Free Full Text]
  17. Brownell, J. E., J. Zhou, T. Ranalli, R. Kobayashi, D. G. Edmondson, S. Y. Roth, C. D. Allis. 1996. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84:843.[Medline]
  18. Taunton, J., C. A. Hassig, S. L. Schreiber. 1996. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272:408.[Abstract]
  19. Lee, G. R., P. E. Fields, R. A. Flavell. 2001. Regulation of IL-4 gene expression by distal regulatory elements and GATA-3 at the chromatin level. Immunity 14:447.[Medline]
  20. Gorelik, L., P. E. Fields, R. A. Flavell. 2000. Cutting edge: TGF-{beta} inhibits Th type 2 development through inhibition of GATA-3 expression. J. Immunol. 165:4773.[Abstract/Free Full Text]
  21. Ranganath, S., W. Ouyang, D. Bhattarcharya, W. C. Sha, A. Grupe, G. Peltz, K. M. Murphy. 1998. GATA-3-dependent enhancer activity in IL-4 gene regulation. J. Immunol. 161:3822.[Abstract/Free Full Text]
  22. Hural, J. A., M. Kwan, G. Henkel, M. B. Hock, M. A. Brown. 2000. An intron transcriptional enhancer element regulates IL-4 gene locus accessibility in mast cells. J. Immunol. 165:3239.[Abstract/Free Full Text]
  23. Mohrs, M., C. M. Blankespoor, Z. E. Wang, G. G. Loots, V. Afzal, H. Hadeiba, K. Shinkai, E. M. Rubin, R. M. Locksley. 2001. Deletion of a coordinate regulator of type 2 cytokine expression in mice. Nat. Immunol. 2:842.[Medline]
  24. Nakamura, T., Y. Kamogawa, K. Bottomly, R. A. Flavell. 1997. Polarization of IL-4- and IFN-{gamma}-producing CD4+ T cells following activation of naive CD4+ T cells. J. Immunol. 158:1085.[Abstract]
  25. Zhao, K., W. Wang, O. J. Rando, Y. Xue, K. Swiderek, A. Kuo, G. R. Crabtree. 1998. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95:625.[Medline]
  26. Mullen, A. C., A. S. Hutchins, A. V. Villarino, H. W. Lee, F. A. High, N. Cereb, S. Y. Yang, X. Hua, S. L. Reiner. 2001. Cell cycle controlling the silencing and functioning of mammalian activators. Curr. Biol. 11:1695.[Medline]
  27. Kaplan, M. H., Y. L. Sun, T. Hoey, M. J. Grusby. 1996. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature 382:174.[Medline]
  28. Agalioti, T., S. Lomvardas, B. Parekh, J. Yie, T. Maniatis, D. Thanos. 2000. Ordered recruitment of chromatin modifying and general transcription factors to the IFN-{beta} promoter. Cell 103:667.[Medline]
  29. Avni, O., A. Rao. 2000. T cell differentiation: a mechanistic view. Curr. Opin. Immunol. 12:654.[Medline]



This article has been cited by other articles:


Home page
 J. Immunol.Home page
Q. Yu, H.-C. Chang, A.-N. N. Ahyi, and M. H. Kaplan
Transcription Factor-Dependent Chromatin Remodeling of Il18r1 during Th1 and Th2 Differentiation
J. Immunol., September 1, 2008; 181(5): 3346 - 3352.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. K. Northrop, A. D. Wells, and H. Shen
Cutting Edge: Chromatin Remodeling as a Molecular Basis for the Enhanced Functionality of Memory CD8 T Cells
J. Immunol., July 15, 2008; 181(2): 865 - 868.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
Y. Zhang, S. Saccani, H. Shin, and B. S. Nikolajczyk
Dynamic Protein Associations Define Two Phases of IL-1{beta} Transcriptional Activation
J. Immunol., July 1, 2008; 181(1): 503 - 512.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
Y. Araki, M. Fann, R. Wersto, and N.-p. Weng
Histone Acetylation Facilitates Rapid and Robust Memory CD8 T Cell Response through Differential Expression of Effector Molecules (Eomesodermin and Its Targets: Perforin and Granzyme B)
J. Immunol., June 15, 2008; 180(12): 8102 - 8108.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
E. Jacob, R. Hod-Dvorai, S. Schif-Zuck, and O. Avni
Unconventional Association of the Polycomb Group Proteins with Cytokine Genes in Differentiated T Helper Cells
J. Biol. Chem., May 9, 2008; 283(19): 13471 - 13481.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
D. Hawiger, E. Tran, W. Du, C. J. Booth, L. Wen, C. Dong, and R. A. Flavell
ICOS Mediates the Development of Insulin-Dependent Diabetes Mellitus in Nonobese Diabetic Mice
J. Immunol., March 1, 2008; 180(5): 3140 - 3147.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S.-Y. Pai, B. Y. Kang, A. M. Sabadini, E. Parisini, M. L. Truitt, and I-C. Ho
Distinct Structural Requirements of GATA-3 for the Regulation of Thymocyte and Th2 Cell Differentiation
J. Immunol., January 15, 2008; 180(2): 1050 - 1059.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
M. D. Lewis, S. A. Miller, M. M. Miazgowicz, K. M. Beima, and A. S. Weinmann
T-bet's Ability To Regulate Individual Target Genes Requires the Conserved T-Box Domain To Recruit Histone Methyltransferase Activity and a Separate Family Member-Specific Transactivation Domain
Mol. Cell. Biol., December 15, 2007; 27(24): 8510 - 8521.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
X. Zhao, B. Zheng, Y. Huang, D. Yang, S. Katzman, C. Chang, D. Fowell, and W.-p. Zeng
Interaction between GATA-3 and the Transcriptional Coregulator Pias1 Is Important for the Regulation of Th2 Immune Responses
J. Immunol., December 15, 2007; 179(12): 8297 - 8304.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
H. K. Hamalainen-Laanaya, J. J. Kobie, C. Chang, and W.-p. Zeng
Temporal and Spatial Changes of Histone 3 K4 Dimethylation at the IFN-{gamma} Gene during Th1 and Th2 Cell Differentiation
J. Immunol., November 15, 2007; 179(10): 6410 - 6415.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Long, A. M. Slaiby, S. Wu, A. T. Hagymasi, M. A. Mihalyo, S. Bandyopadhyay, A. T. Vella, and A. J. Adler
Histone Acetylation at the Ifng Promoter in Tolerized CD4 Cells Is Associated with Increased IFN-{gamma} Expression during Subsequent Immunization to the Same Antigen
J. Immunol., November 1, 2007; 179(9): 5669 - 5677.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. T. Kim, P. E. Fields, and R. A. Flavell
Demethylation of a specific hypersensitive site in the Th2 locus control region
PNAS, October 23, 2007; 104(43): 17052 - 17057.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. E. Gazzar, B. K. Yoza, J. Y.-Q. Hu, S. L. Cousart, and C. E. McCall
Epigenetic Silencing of Tumor Necrosis Factor {alpha} during Endotoxin Tolerance
J. Biol. Chem., September 14, 2007; 282(37): 26857 - 26864.
[Abstract] [Full Text] [PDF]

Home page
 J. Exp. Med.Home page
W. Li, M. H. Sofi, N. Yeh, S. Sehra, B. P. McCarthy, D. R. Patel, R. R. Brutkiewicz, M. H. Kaplan, and C.-H. Chang
Thymic selection pathway regulates the effector function of CD4 T cells
J. Exp. Med., September 3, 2007; 204(9): 2145 - 2157.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. L. Matsuda, T. C. George, J. Hagman, and L. Gapin
Temporal Dissection of T-bet Functions
J. Immunol., March 15, 2007; 178(6): 3457 - 3465.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. Radhakrishnan, K. R. Wiehagen, V. Pulko, V. Van Keulen, W. A. Faubion, K. L. Knutson, and L. R. Pease
Induction of a Th1 Response from Th2-Polarized T Cells by Activated Dendritic Cells: Dependence on TCR:Peptide-MHC Interaction, ICAM-1, IL-12, and IFN-{gamma}
J. Immunol., March 15, 2007; 178(6): 3583 - 3592.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
B. Li, A. Samanta, X. Song, K. T. Iacono, K. Bembas, R. Tao, S. Basu, J. L. Riley, W. W. Hancock, Y. Shen, et al.
FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression
PNAS, March 13, 2007; 104(11): 4571 - 4576.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. Rose, M. Lichtenheld, M. R. Foote, and B. Adkins
Murine Neonatal CD4+ Cells Are Poised for Rapid Th2 Effector-Like Function
J. Immunol., March 1, 2007; 178(5): 2667 - 2678.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
L. Chen, W. He, S. T. Kim, J. Tao, Y. Gao, H. Chi, A. M. Intlekofer, B. Harvey, S. L. Reiner, Z. Yin, et al.
Epigenetic and Transcriptional Programs Lead to Default IFN-{gamma} Production by {gamma}{delta} T Cells
J. Immunol., March 1, 2007; 178(5): 2730 - 2736.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Fann, J. M. Godlove, M. Catalfamo, W. H. Wood III, F. J. Chrest, N. Chun, L. Granger, R. Wersto, K. Madara, K. Becker, et al.
Histone acetylation is associated with differential gene expression in the rapid and robust memory CD8+ T-cell response
Blood, November 15, 2006; 108(10): 3363 - 3370.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
S. Agaugue, L. Perrin-Cocon, F. Coutant, P. Andre, and V. Lotteau
1-Methyl-Tryptophan Can Interfere with TLR Signaling in Dendritic Cells Independently of IDO Activity
J. Immunol., August 15, 2006; 177(4): 2061 - 2071.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. K. Northrop, R. M. Thomas, A. D. Wells, and H. Shen
Epigenetic Remodeling of the IL-2 and IFN-{gamma} Loci in Memory CD8 T Cells Is Influenced by CD4 T Cells
J. Immunol., July 15, 2006; 177(2): 1062 - 1069.
[Abstract] [Full Text] [PDF]

Home page
 J. Exp. Med.Home page
F. Zhang and M. Boothby
T helper type 1-specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-{gamma} promoter are Stat4 dependent
J. Exp. Med., June 12, 2006; 203(6): 1493 - 1505.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
T. Hayashida, M. Oda, K. Ohsawa, A. Yamaguchi, T. Hosozawa, R. M. Locksley, M. Giacca, H. Masai, and S. Miyatake
Replication Initiation from a Novel Origin Identified in the Th2 Cytokine Cluster Locus Requires a Distant Conserved Noncoding Sequence
J. Immunol., May 1, 2006; 176(9): 5446 - 5454.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. D. Liang, Y. Zhang, D. McDevit, S. Marecki, and B. S. Nikolajczyk
The Interleukin-1beta Gene Is Transcribed from a Poised Promoter Architecture in Monocytes
J. Biol. Chem., April 7, 2006; 281(14): 9227 - 9237.
[Abstract] [Full Text] [PDF]

Home page
 Int ImmunolHome page
C. M. Tato, N. Mason, D. Artis, S. Shapira, J. C. Caamano, J. H. Bream, H.-C. Liou, and C. A. Hunter
Opposing roles of NF-{kappa}B family members in the regulation of NK cell proliferation and production of IFN-{gamma}
Int. Immunol., April 1, 2006; 18(4): 505 - 513.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
E. N. Kersh, D. R. Fitzpatrick, K. Murali-Krishna, J. Shires, S. H. Speck, J. M. Boss, and R. Ahmed
Rapid Demethylation of the IFN-{gamma} Gene Occurs in Memory but Not Naive CD8 T Cells
J. Immunol., April 1, 2006; 176(7): 4083 - 4093.
[Abstract] [Full Text] [PDF]

Home page
 J. Exp. Med.Home page
T. Usui, J. C. Preiss, Y. Kanno, Z. J. Yao, J. H. Bream, J. J. O'Shea, and W. Strober
T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription
J. Exp. Med., March 20, 2006; 203(3): 755 - 766.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
M. Long, A. M. Slaiby, A. T. Hagymasi, M. A. Mihalyo, A. C. Lichtler, S. L. Reiner, and A. J. Adler
T-bet Down-Modulation in Tolerized Th1 Effector CD4 Cells Confers a TCR-Distal Signaling Defect That Selectively Impairs IFN-{gamma} Expression
J. Immunol., January 15, 2006; 176(2): 1036 - 1045.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Baguet, X. Sun, T. Arroll, A. Krumm, and M. Bix
Intergenic Transcription Is Not Required in Th2 Cells to Maintain Histone Acetylation and Transcriptional Permissiveness at the Il4-Il13 Locus
J. Immunol., December 15, 2005; 175(12): 8146 - 8153.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Chang and T. M. Aune
Histone hyperacetylated domains across the Ifng gene region in natural killer cells and T cells
PNAS, November 22, 2005; 102(47): 17095 - 17100.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Yamashita, R. Shinnakasu, H. Asou, M. Kimura, A. Hasegawa, K. Hashimoto, N. Hatano, M. Ogata, and T. Nakayama
Ras-ERK MAPK Cascade Regulates GATA3 Stability and Th2 Differentiation through Ubiquitin-Proteasome Pathway
J. Biol. Chem., August 19, 2005; 280(33): 29409 - 29419.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
L.-O. Tykocinski, P. Hajkova, H.-D. Chang, T. Stamm, O. SOzeri, M. LOhning, J. Hu-Li, U. Niesner, S. Kreher, B. Friedrich, et al.
A Critical Control Element for Interleukin-4 Memory Expression in T Helper Lymphocytes
J. Biol. Chem., August 5, 2005; 280(31): 28177 - 28185.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.