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Interplay between Chromatin Remodeling and Epigenetic Changes during Lineage-Specific Commitment to Granzyme B Expression¹

Torsten Juelich,^* Elissa Sutcliffe,^* Alice Denton, Yiqing He,^* Peter C. Doherty, Christopher Parish,^* Steven J. Turner,^* David Tremethick, and Sudha Rao²

^*Division of Immunology and Genetics and Division of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra, Australia; and Department of Microbiology and Immunology, University of Melbourne, Melbourne, Victoria, Australia

The role of chromatin remodeling and histone posttranslational modifications and how they are integrated to control gene expression during the acquisition of cell-specific functions is poorly understood. We show here that following in vitro activation of CD4⁺ and CD8⁺ T lymphocytes, both cell types show rapid histone H3 loss at the granzyme B (gzmB) proximal promoter region. However, despite the gzmB proximal promoter being remodeled in both T cell subsets, only CD8⁺ T cells express high levels of gzmB and display a distinct pattern of key epigenetic marks, notably differential H3 acetylation and methylation. These data suggest that for high levels of transcription to occur a distinct set of histone modifications needs to be established in addition to histone loss at the proximal promoter of gzmB.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by Australian National Health and Medical Research Council Project Grant 454455, National Health and Medical Research Council Program Grants 299907 and 455395, a National Health and Medical Research Council Dora Lush Postgraduate Fellowship awarded to A.D., and a Pfizer Senior Research Fellowship awarded to S.J.T.

² Address correspondence and reprint requests to Dr. Sudha Rao, Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, GPO Box 334, Canberra City ACT 2601 Australia. E-mail address: sudha.rao{at}anu.edu.au

³ Abbreviations used in this paper: gzmB, granzyme B; gzmN, granzyme N; TF, transcription factor; Pol II, polymerase II; ChIP, chromatin immunoprecipitation; CHART, chromatin accessibility and real time; Ct, threshold cycle; Mnase, micrococcal nuclease; H3K9acet, H3K9 acetylation; TSS, transcriptional start site; PTM, posttranscriptional modification E-Pol II.

⁴ The online version of this article contains supplemental material.