The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease.

Shan He, Fang Xie, Yongnian Liu, Qing Tong, Kazuhiro Mochizuki, Philip E. Lapinski, Ram Shankar Mani, Pavan Reddy, Izumi Mochizuki, Arul M. Chinnaiyan, Shin Mineishi, Philip D. King, Y. Zhang

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Posttranscriptional modification of histones by methylation plays an important role in regulating Ag-driven T-cell responses. We have recently drawn correlations between allogeneic T-cell responses and the histone methyltransferase Ezh2, which catalyzes histone H3 lysine 27 trimethylation. The functional relevance of Ezh2 in T-cell alloimmunity remains unclear. Here, we identify a central role of Ezh2 in regulating allogeneic T-cell proliferation, differentiation, and function. Conditional loss of Ezh2 in donor T cells inhibited graft-versus-host disease (GVHD) in mice after allogeneic bone marrow (BM) transplantation. Although Ezh2-deficient T cells were initially activated to proliferate upon alloantigenic priming, their ability to undergo continual proliferation and expansion was defective during late stages of GVHD induction. This effect of Ezh2 ablation was largely independent of the proapoptotic molecule Bim. Unexpectedly, as a gene silencer, Ezh2 was required to promote the expression of transcription factors Tbx21 and Stat4. Loss of Ezh2 in T cells specifically impaired their differentiation into interferon (IFN)-γ-producing effector cells. However, Ezh2 ablation retained antileukemia activity in alloreactive T cells, leading to improved overall survival of the recipients. Our findings justify investigation of modulating Ezh2 as a therapeutic strategy for the treatment of GVHD and other T cell-mediated inflammatory disorders.

Original languageEnglish (US)
Pages (from-to)4119-4128
Number of pages10
JournalBlood
Volume122
Issue number25
StatePublished - Dec 12 2013

Fingerprint

T-cells
Graft vs Host Disease
Epigenomics
Grafts
T-Lymphocytes
Ablation
Histones
Histone Code
histone methyltransferase
Methylation
Homologous Transplantation
Cell proliferation
Bone Marrow Transplantation
Interferons
Lysine
Cell Differentiation
Bone
Transcription Factors
Genes
Cell Proliferation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

Cite this

He, S., Xie, F., Liu, Y., Tong, Q., Mochizuki, K., Lapinski, P. E., ... Zhang, Y. (2013). The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease. Blood, 122(25), 4119-4128.

The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease. / He, Shan; Xie, Fang; Liu, Yongnian; Tong, Qing; Mochizuki, Kazuhiro; Lapinski, Philip E.; Mani, Ram Shankar; Reddy, Pavan; Mochizuki, Izumi; Chinnaiyan, Arul M.; Mineishi, Shin; King, Philip D.; Zhang, Y.

In: Blood, Vol. 122, No. 25, 12.12.2013, p. 4119-4128.

Research output: Contribution to journalArticle

He, S, Xie, F, Liu, Y, Tong, Q, Mochizuki, K, Lapinski, PE, Mani, RS, Reddy, P, Mochizuki, I, Chinnaiyan, AM, Mineishi, S, King, PD & Zhang, Y 2013, 'The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease.', Blood, vol. 122, no. 25, pp. 4119-4128.
He, Shan ; Xie, Fang ; Liu, Yongnian ; Tong, Qing ; Mochizuki, Kazuhiro ; Lapinski, Philip E. ; Mani, Ram Shankar ; Reddy, Pavan ; Mochizuki, Izumi ; Chinnaiyan, Arul M. ; Mineishi, Shin ; King, Philip D. ; Zhang, Y. / The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease. In: Blood. 2013 ; Vol. 122, No. 25. pp. 4119-4128.
@article{dd0b69b01b594078b16d6328a982a07e,
title = "The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease.",
abstract = "Posttranscriptional modification of histones by methylation plays an important role in regulating Ag-driven T-cell responses. We have recently drawn correlations between allogeneic T-cell responses and the histone methyltransferase Ezh2, which catalyzes histone H3 lysine 27 trimethylation. The functional relevance of Ezh2 in T-cell alloimmunity remains unclear. Here, we identify a central role of Ezh2 in regulating allogeneic T-cell proliferation, differentiation, and function. Conditional loss of Ezh2 in donor T cells inhibited graft-versus-host disease (GVHD) in mice after allogeneic bone marrow (BM) transplantation. Although Ezh2-deficient T cells were initially activated to proliferate upon alloantigenic priming, their ability to undergo continual proliferation and expansion was defective during late stages of GVHD induction. This effect of Ezh2 ablation was largely independent of the proapoptotic molecule Bim. Unexpectedly, as a gene silencer, Ezh2 was required to promote the expression of transcription factors Tbx21 and Stat4. Loss of Ezh2 in T cells specifically impaired their differentiation into interferon (IFN)-γ-producing effector cells. However, Ezh2 ablation retained antileukemia activity in alloreactive T cells, leading to improved overall survival of the recipients. Our findings justify investigation of modulating Ezh2 as a therapeutic strategy for the treatment of GVHD and other T cell-mediated inflammatory disorders.",
author = "Shan He and Fang Xie and Yongnian Liu and Qing Tong and Kazuhiro Mochizuki and Lapinski, {Philip E.} and Mani, {Ram Shankar} and Pavan Reddy and Izumi Mochizuki and Chinnaiyan, {Arul M.} and Shin Mineishi and King, {Philip D.} and Y. Zhang",
year = "2013",
month = "12",
day = "12",
language = "English (US)",
volume = "122",
pages = "4119--4128",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "25",

}

TY - JOUR

T1 - The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease.

AU - He, Shan

AU - Xie, Fang

AU - Liu, Yongnian

AU - Tong, Qing

AU - Mochizuki, Kazuhiro

AU - Lapinski, Philip E.

AU - Mani, Ram Shankar

AU - Reddy, Pavan

AU - Mochizuki, Izumi

AU - Chinnaiyan, Arul M.

AU - Mineishi, Shin

AU - King, Philip D.

AU - Zhang, Y.

PY - 2013/12/12

Y1 - 2013/12/12

N2 - Posttranscriptional modification of histones by methylation plays an important role in regulating Ag-driven T-cell responses. We have recently drawn correlations between allogeneic T-cell responses and the histone methyltransferase Ezh2, which catalyzes histone H3 lysine 27 trimethylation. The functional relevance of Ezh2 in T-cell alloimmunity remains unclear. Here, we identify a central role of Ezh2 in regulating allogeneic T-cell proliferation, differentiation, and function. Conditional loss of Ezh2 in donor T cells inhibited graft-versus-host disease (GVHD) in mice after allogeneic bone marrow (BM) transplantation. Although Ezh2-deficient T cells were initially activated to proliferate upon alloantigenic priming, their ability to undergo continual proliferation and expansion was defective during late stages of GVHD induction. This effect of Ezh2 ablation was largely independent of the proapoptotic molecule Bim. Unexpectedly, as a gene silencer, Ezh2 was required to promote the expression of transcription factors Tbx21 and Stat4. Loss of Ezh2 in T cells specifically impaired their differentiation into interferon (IFN)-γ-producing effector cells. However, Ezh2 ablation retained antileukemia activity in alloreactive T cells, leading to improved overall survival of the recipients. Our findings justify investigation of modulating Ezh2 as a therapeutic strategy for the treatment of GVHD and other T cell-mediated inflammatory disorders.

AB - Posttranscriptional modification of histones by methylation plays an important role in regulating Ag-driven T-cell responses. We have recently drawn correlations between allogeneic T-cell responses and the histone methyltransferase Ezh2, which catalyzes histone H3 lysine 27 trimethylation. The functional relevance of Ezh2 in T-cell alloimmunity remains unclear. Here, we identify a central role of Ezh2 in regulating allogeneic T-cell proliferation, differentiation, and function. Conditional loss of Ezh2 in donor T cells inhibited graft-versus-host disease (GVHD) in mice after allogeneic bone marrow (BM) transplantation. Although Ezh2-deficient T cells were initially activated to proliferate upon alloantigenic priming, their ability to undergo continual proliferation and expansion was defective during late stages of GVHD induction. This effect of Ezh2 ablation was largely independent of the proapoptotic molecule Bim. Unexpectedly, as a gene silencer, Ezh2 was required to promote the expression of transcription factors Tbx21 and Stat4. Loss of Ezh2 in T cells specifically impaired their differentiation into interferon (IFN)-γ-producing effector cells. However, Ezh2 ablation retained antileukemia activity in alloreactive T cells, leading to improved overall survival of the recipients. Our findings justify investigation of modulating Ezh2 as a therapeutic strategy for the treatment of GVHD and other T cell-mediated inflammatory disorders.

UR - http://www.scopus.com/inward/record.url?scp=84893482395&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84893482395&partnerID=8YFLogxK

M3 - Article

VL - 122

SP - 4119

EP - 4128

JO - Blood

JF - Blood

SN - 0006-4971

IS - 25

ER -