Deciphering the role of histone modifications in memory and exhausted CD8 T cells
Exhausted CD8 T cells (T<sub>EX</sub>) 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 (T<sub>MEM</sub>) cells, T<sub>EX</sub> have a unique open chromatin landscape underlying a distinct gene expression program. How T<sub>EX</sub> 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 (T<sub>N</sub>), T<sub>MEM</sub> and T<sub>EX</sub>. We identified H3K27ac-associated super-enhancers that distinguish T<sub>N</sub>, T<sub>MEM</sub> and T<sub>EX</sub>, along with key transcription factor networks predicted to regulate these different transcriptional landscapes. Promoters of some key genes were poised in T<sub>N</sub>, but activated in T<sub>MEM</sub> or T<sub>EX</sub> whereas other genes poised in T<sub>N</sub> were repressed in T<sub>MEM</sub> or T<sub>EX</sub>, 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 T<sub>EX</sub>, suggesting an atypical role for this modification. These data indicate that beyond chromatin accessibility, hPTMs differentially regulate specific gene expression programs of T<sub>EX</sub> compared to T<sub>MEM</sub> through both activating and repressive pathways.
Authors
- Parisa Samareh
- Shelley L. Berger (ORCID: https://orcid.org/0000-0001-5398-4400)
- Zhen Zhang (ORCID: https://orcid.org/0000-0001-8057-7624)
- Junwei Shi (ORCID: https://orcid.org/0000-0002-8427-6316)
- Charly R. Good (ORCID: https://orcid.org/0000-0002-9934-9696)
- Karl M. Glastad (ORCID: https://orcid.org/0000-0002-8142-1821)
- E. John Wherry (ORCID: https://orcid.org/0000-0003-0477-1956)
- Sierra M. Collins (ORCID: https://orcid.org/0000-0002-8174-9659)
- Josephine R. Giles (ORCID: https://orcid.org/0000-0002-3713-338X)
- Amy E. Baxter (ORCID: https://orcid.org/0000-0002-1555-0713)
- Katherine A. Alexander (ORCID: https://orcid.org/0000-0002-0655-5432)
- Lu Wang (ORCID: https://orcid.org/0000-0002-4398-122X)
- Hua Huang (ORCID: https://orcid.org/0000-0002-8936-3371)
- Sasikanth Manne (ORCID: https://orcid.org/0000-0001-9856-0871)
- Zeyu Chen (ORCID: https://orcid.org/0000-0001-6393-1986)
- Paula A. Agudelo Garcia (ORCID: https://orcid.org/0000-0003-2810-9131)
- Gregory Donahue
Institutions
- Broad Institute (US)
- Children's Hospital of Philadelphia (US)
- Harvard University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Cancer Research Institute (US)
- Cold Spring Harbor Laboratory (US)
- Parker Institute for Cancer Immunotherapy (US)
- Dana-Farber Cancer Institute (US)
- Translational Therapeutics (United States) (US)
- UPMC Hillman Cancer Center (US)
- Harvard Stem Cell Institute (US)
- The Ohio State University (US)
- University of Rochester (US)
- University of Pennsylvania (US)
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-05-19
- DOI
- https://doi.org/10.1038/s41598-025-99804-0
- Citations
- 5
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 3.99
Funders
- Celgene
- Parker Institute for Cancer Immunotherapy
- National Institutes of Health