Deciphering the role of histone modifications in memory and exhausted CD8 T cells

被引：0

作者：

Huang, Hua ^{[1
,2
,3
,4
]}

Baxter, Amy E. ^{[1
,2
,5
]}

Zhang, Zhen ^{[3
,4
,6
]}

Good, Charly R. ^{[3
,4
]}

Alexander, Katherine A. ^{[3
,4
,7
]}

Chen, Zeyu ^{[1
,2
,8
,9
,10
]}

Garcia, Paula A. Agudelo ^{[3
,4
,11
]}

Samareh, Parisa ^{[3
,4
]}

Collins, Sierra M. ^{[3
,4
]}

Glastad, Karl M. ^{[3
,4
,12
]}

Wang, Lu ^{[3
,4
,13
,14
]}

Donahue, Gregory ^{[3
,4
]}

Manne, Sasikanth ^{[1
,2
]}

Giles, Josephine R. ^{[1
,2
,19
]}

Shi, Junwei ^{[3
,15
,16
]}

Berger, Shelley L. ^{[3
,4
,17
,18
]}

Wherry, E. John ^{[1
,2
,19
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA

[2] Univ Penn, Perelman Sch Med, Inst Immunol & Immune Hlth, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Epigenet Inst, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA

[5] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[6] Hefei Comprehens Natl Sci Ctr, Inst Hlth & Med, Hefei 230601, Anhui, Peoples R China

[7] Cold Spring Harbor Labs, Cold Spring Harbor, NY 11724 USA

[8] Broad Inst MIT & Harvard, Gene Regulat Observ, Cambridge, MA 02142 USA

[9] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[10] Harvard Med Sch, Dept Cell Biol & Pathol, Boston, MA 02115 USA

[11] Ohio State Univ, Dept Biomed Engn, Columbus, OH 43210 USA

[12] Univ Rochester, Dept Biol, Rochester, NY 14620 USA

[13] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA

[14] Univ Texas Hlth Sci Ctr San Antonio, Dept Biochem & Struct Biol, San Antonio, TX 78229 USA

[15] Univ Penn, Perelman Sch Med, Dept Canc Biol, Philadelphia, PA USA

[16] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA USA

[17] Univ Penn, Perelman Sch Med, Dept Genet, Philadelphia, PA 19104 USA

[18] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA

[19] Univ Penn, Parker Inst Canc Immunotherapy, Philadelphia, PA 19104 USA

来源：

SCIENTIFIC REPORTS | 2025年 / 15卷 / 01期

基金：

美国国家卫生研究院;

关键词：

TRANSCRIPTION FACTORS; TERMINAL DIFFERENTIATION; EPIGENETIC LANDSCAPE; SUPER-ENHANCERS; DNA METHYLATION; CHROMATIN-STATE; VIRAL-INFECTION; EFFECTOR; PD-1; IDENTITY;

D O I：

10.1038/s41598-025-99804-0

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Exhausted CD8 T cells (TEX) arising during chronic infections and cancer have reduced functional capacity and limited fate flexibility that prevents optimal disease control and response to immunotherapies. Compared to memory (TMEM) cells, TEX have a unique open chromatin landscape underlying a distinct gene expression program. How TEX transcriptional and epigenetic landscapes are regulated through histone post-translational modifications (hPTMs) remains unclear. Here, we profiled key activating (H3K27ac and H3K4me3) and repressive (H3K27me3 and H3K9me3) histone modifications in naive CD8 T cells (TN), TMEM and TEX. We identified H3K27ac-associated super-enhancers that distinguish TN, TMEM and TEX, along with key transcription factor networks predicted to regulate these different transcriptional landscapes. Promoters of some key genes were poised in TN, but activated in TMEM or TEX whereas other genes poised in TN were repressed in TMEM or TEX, indicating that both repression and activation of poised genes may enforce these distinct cell states. Moreover, narrow peaks of repressive H3K9me3 were associated with increased gene expression in TEX, suggesting an atypical role for this modification. These data indicate that beyond chromatin accessibility, hPTMs differentially regulate specific gene expression programs of TEX compared to TMEM through both activating and repressive pathways.

引用

页数：22

共 145 条

[21] In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer [J].

Chen, Zeyu ;

Arai, Eri ;

Khan, Omar ;

Zhang, Zhen ;

Ngiow, Shin Foong ;

He, Yuan ;

Huang, Hua ;

Manne, Sasikanth ;

Cao, Zhendong ;

Baxter, Amy E. ;

Cai, Zhangying ;

Freilich, Elizabeth ;

Ali, Mohammed A. ;

Giles, Josephine R. ;

Wu, Jennifer E. ;

Greenplate, Allison R. ;

Hakeem, Mohamed A. ;

Chen, Qingzhou ;

Kurachi, Makoto ;

Nzingha, Kito ;

Ekshyyan, Viktoriya ;

Mathew, Divij ;

Wen, Zhuoyu ;

Speck, Nancy A. ;

Battle, Alexis ;

Berger, Shelley L. ;

Wherry, E. John ;

Shi, Junwei .

CELL, 2021, 184 (05) :1262-+

[22] TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision [J].

Chen, Zeyu ;

Ji, Zhicheng ;

Ngiow, Shin Foong ;

Manne, Sasikanth ;

Cai, Zhangying ;

Huang, Alexander C. ;

Johnson, John ;

Staupe, Ryan P. ;

Bengsch, Bertram ;

Xu, Caiyue ;

Yu, Sixiang ;

Kurachi, Makoto ;

Herati, Ramin S. ;

Vella, Laura A. ;

Baxter, Amy E. ;

Wu, Jennifer E. ;

Khan, Omar ;

Beltra, Jean-Christophe ;

Giles, Josephine R. ;

Stelekati, Erietta ;

McLane, Laura M. ;

Lau, Chi Wai ;

Yang, Xiaolu ;

Berger, Shelley L. ;

Vahedi, Golnaz ;

Ji, Hongkai ;

Wherry, E. John .

IMMUNITY, 2019, 51 (05) :840-+

[23] Histone H3K27ac separates active from poised enhancers and predicts developmental state [J].

Creyghton, Menno P. ;

Cheng, Albert W. ;

Welstead, G. Grant ;

Kooistra, Tristan ;

Carey, Bryce W. ;

Steine, Eveline J. ;

Hanna, Jacob ;

Lodato, Michael A. ;

Frampton, Garrett M. ;

Sharp, Phillip A. ;

Boyer, Laurie A. ;

Young, Richard A. ;

Jaenisch, Rudolf .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (50) :21931-21936

[24] PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors [J].

Curran, Michael A. ;

Montalvo, Welby ;

Yagita, Hideo ;

Allison, James P. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (09) :4275-4280

[25] Twelve years of SAMtools and BCFtools [J].

Danecek, Petr ;

Bonfield, James K. ;

Liddle, Jennifer ;

Marshall, John ;

Ohan, Valeriu ;

Pollard, Martin O. ;

Whitwham, Andrew ;

Keane, Thomas ;

McCarthy, Shane A. ;

Davies, Robert M. ;

Li, Heng .

GIGASCIENCE, 2021, 10 (02)

[26] Divergent clonal differentiation trajectories of T cell exhaustion [J].

Daniel, Bence ;

Yost, Kathryn E. ;

Hsiung, Sunnie ;

Sandor, Katalin ;

Xia, Yu ;

Qi, Yanyan ;

Hiam-Galvez, Kamir J. ;

Black, Mollie ;

Raposo, Colin J. ;

Shi, Quanming ;

Meier, Stefanie L. ;

Belk, Julia A. ;

Giles, Josephine R. ;

Wherry, E. John ;

Chang, Howard Y. ;

Egawa, Takeshi ;

Satpathy, Ansuman T. .

NATURE IMMUNOLOGY, 2022, 23 (11) :1614-+

[27] Transposable elements contribute to cell and species-specific chromatin looping and gene regulation in mammalian genomes [J].

Diehl, Adam G. ;

Ouyang, Ningxin ;

Boyle, Alan P. .

NATURE COMMUNICATIONS, 2020, 11 (01)

[28] TET2 regulates early and late transitions in exhausted CD8+ T cell differentiation and limits CAR T cell function [J].

Dimitri, Alexander J. ;

Baxter, Amy E. ;

Chen, Gregory M. ;

Hopkins, Caitlin R. ;

Rouin, Geoffrey T. ;

Huang, Hua ;

Kong, Weimin ;

Holliday, Christopher H. ;

Wiebking, Volker ;

Bartoszek, Robert ;

Drury, Sydney ;

Dalton, Katherine ;

Koucky, Owen M. ;

Chen, Zeyu ;

Giles, Josephine R. ;

Dils, Alexander T. ;

Jung, In-Young ;

O'Connor, Roddy ;

Collins, Sierra ;

Everett, John K. ;

Amses, Kevin ;

Sherrill-Mix, Scott ;

Chandra, Aditi ;

Goldman, Naomi ;

Vahedi, Golnaz ;

Jadlowsky, Julie K. ;

Young, Regina M. ;

Melenhorst, Jan Joseph ;

Maude, Shannon L. ;

Levine, Bruce L. ;

Frey, Noelle V. ;

Berger, Shelley L. ;

Grupp, Stephan A. ;

Porter, David L. ;

Herbst, Friederike ;

Porteus, Matthew H. ;

Carty, Shannon A. ;

Bushman, Frederic D. ;

Weber, Evan W. ;

Wherry, E. John ;

Jordan, Martha S. ;

Fraietta, Joseph A. .

SCIENCE ADVANCES, 2024, 10 (46)

[29] STAR: ultrafast universal RNA-seq aligner [J].

Dobin, Alexander ;

Davis, Carrie A. ;

Schlesinger, Felix ;

Drenkow, Jorg ;

Zaleski, Chris ;

Jha, Sonali ;

Batut, Philippe ;

Chaisson, Mark ;

Gingeras, Thomas R. .

BIOINFORMATICS, 2013, 29 (01) :15-21

[30] The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection [J].

Dominguez, Claudia X. ;

Amezquita, Robert A. ;

Guan, Tianxia ;

Marshall, Heather D. ;

Joshi, Nikhil S. ;

Kleinstein, Steven H. ;

Kaech, Susan M. .

JOURNAL OF EXPERIMENTAL MEDICINE, 2015, 212 (12) :2041-2056

← 1 2 3 4 5 6 7 8 9 10 →