The differentiation of T helper cell subsets and their acquisition of effector functions are accompanied by changes in gene expression programmes, which in part are regulated and maintained by epigenetic processes. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are key epigenetic regulators that function by mediating dynamic changes in the acetylation of histones at lysine residues. In addition, many non-histone proteins are also acetylated, and reversible acetylation affects their functional properties, demonstrating that HDACs mediate effects beyond the epigenetic regulation of gene expression. In this Review, we discuss studies revealing that HDACs are key regulators of CD4+ T cell-mediated immunity in mice and humans and that HDACs are promising targets in T cell-mediated immune diseases. Finally, we discuss unanswered questions and future research directions to promote the concept that isoform-selective HDAC inhibitors might broaden the clinical application of HDAC inhibitors beyond their current use in certain types of cancer.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Wang, Z. et al. Combinatorial patterns of histone acetylations and methylations in the human genome. Nat. Genet. 40, 897–903 (2008). This study investigates the extent to which gene-specific combinatorial patterns of histone modifications exist in promoter and enhancer regions of human CD4 + T cells and identifies a common modification module consisting of 17 modifications detected at 3,286 promoters, suggesting that various histone modifications act cooperatively to prepare chromatin for transcriptional activation.
Norvell, A. & McMahon, S. B. Cell biology. Rise of the rival. Science 327, 964–965 (2010).
Choudhary, C., Weinert, B. T., Nishida, Y., Verdin, E. & Mann, M. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat. Rev. Mol. Cell Biol. 15, 536–550 (2014).
Drazic, A., Myklebust, L. M., Ree, R. & Arnesen, T. The world of protein acetylation. Biochim. Biophys. Acta 1864, 1372–1401 (2016).
Phillips, D. M. The presence of acetyl groups of histones. Biochem. J. 87, 258–263 (1963).
Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).
Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011). This work reports the identification of many previously undescribed histone modifications, including lysine crotonylation, which mark either active promoters or potential enhancers in human somatic and mouse male germ cell genomes.
Seto, E. & Yoshida, M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6, a018713 (2014).
Zheng, Y., Thomas, P. M. & Kelleher, N. L. Measurement of acetylation turnover at distinct lysines in human histones identifies long-lived acetylation sites. Nat. Commun. 4, 2203 (2013).
Marmorstein, R. & Zhou, M. M. Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb. Perspect. Biol. 6, a018762 (2014).
Sabari, B. R., Zhang, D., Allis, C. D. & Zhao, Y. Metabolic regulation of gene expression through histone acylations. Nat. Rev. Mol. Cell Biol. 18, 90–101 (2017).
Fujisawa, T. & Filippakopoulos, P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat. Rev. Mol. Cell Biol. 18, 246–262 (2017).
Lee, K. K. & Workman, J. L. Histone acetyltransferase complexes: one size doesn’t fit all. Nat. Rev. Mol. Cell Biol. 8, 284–295 (2007).
Xing, S. et al. Tcf1 and Lef1 transcription factors establish CD8+ T cell identity through intrinsic HDAC activity. Nat. Immunol. 17, 695–703 (2016).
Kelly, R. D. & Cowley, S. M. The physiological roles of histone deacetylase (HDAC) 1 and 2: complex co-stars with multiple leading parts. Biochem. Soc. Trans. 41, 741–749 (2013).
Millard, C. J., Watson, P. J., Fairall, L. & Schwabe, J. W. R. Targeting class I histone deacetylases in a “complex” environment. Trends Pharmacol. Sci. 38, 363–377 (2017).
Joshi, P. et al. The functional interactome landscape of the human histone deacetylase family. Mol. Systems Biol. 9, 672 (2013).
Segre, C. V. & Chiocca, S. Regulating the regulators: the post-translational code of class I HDAC1 and HDAC2. J. Biomed. Biotechnol. 2011, 690848 (2011).
Buler, M., Andersson, U. & Hakkola, J. Who watches the watchmen? Regulation of the expression and activity of sirtuins. FASEB J. 30, 3942–3960 (2016).
Gregoretti, I. V., Lee, Y. M. & Goodson, H. V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J. Mol. Biol. 338, 17–31 (2004).
Taplick, J. et al. Homo-oligomerisation and nuclear localisation of mouse histone deacetylase 1. J. Mol. Biol. 308, 27–38 (2001).
Hassig, C. A. et al. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc. Natl Acad. Sci. USA 95, 3519–3524 (1998).
Moser, M. A., Hagelkruys, A. & Seiser, C. Transcription and beyond: the role of mammalian class I lysine deacetylases. Chromosoma 123, 67–78 (2014).
Alland, L. et al. Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature 387, 49–55 (1997).
Ballas, N. et al. Regulation of neuronal traits by a novel transcriptional complex. Neuron 31, 353–365 (2001).
Heinzel, T. et al. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387, 43–48 (1997).
Laherty, C. D. et al. Histone deacetylases associated with the mSin3 corepressor mediate mad transcriptional repression. Cell 89, 349–356 (1997).
Zhang, Y., Iratni, R., Erdjument-Bromage, H., Tempst, P. & Reinberg, D. Histone deacetylases and SAP18, a novel polypeptide, are components of a human Sin3 complex. Cell 89, 357–364 (1997).
Guenther, M. G. et al. A core SMRT corepressor complex containing HDAC3 and TBL1, a WD40-repeat protein linked to deafness. Genes Dev. 14, 1048–1057 (2000).
Guenther, M. G., Barak, O. & Lazar, M. A. The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol. Cell. Biol. 21, 6091–6101 (2001).
Verdin, E., Dequiedt, F. & Kasler, H. G. Class II histone deacetylases: versatile regulators. Trends Genet. 19, 286–293 (2003).
Hudson, G. M., Watson, P. J., Fairall, L., Jamieson, A. G. & Schwabe, J. W. Insights into the recruitment of class IIa histone deacetylases (HDACs) to the SMRT/NCoR transcriptional repression complex. J. Biol. Chem. 290, 18237–18244 (2015).
Haberland, M., Montgomery, R. L. & Olson, E. N. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat. Rev. Genet. 10, 32–42 (2009).
Qiu, Y. et al. HDAC1 acetylation is linked to progressive modulation of steroid receptor-induced gene transcription. Mol. Cell 22, 669–679 (2006).
Dobbin, M. M. et al. SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nat. Neurosci. 16, 1008–1015 (2013).
Peng, L. et al. SIRT1 negatively regulates the activities, functions, and protein levels of hMOF and TIP60. Mol. Cell. Biol. 32, 2823–2836 (2012).
Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 325, 834–840 (2009). This work provides an analysis of global lysine acetylation sites on proteins in several human cell lines and reveals that lysine acetylation preferentially targets large macromolecular complexes involved in diverse cellular processes, indicating that lysine acetylation is broad and comparable to other major post-translational modifications.
Lundby, A. et al. Proteomic analysis of lysine acetylation sites in rat tissues reveals organ specificity and subcellular patterns. Cell Rep. 2, 419–431 (2012).
Caron, C., Boyault, C. & Khochbin, S. Regulatory cross-talk between lysine acetylation and ubiquitination: role in the control of protein stability. Bioessays 27, 408–415 (2005).
Yang, X. J. & Seto, E. Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol. Cell 31, 449–461 (2008).
Lee, J. S., Smith, E. & Shilatifard, A. The language of histone crosstalk. Cell 142, 682–685 (2010).
Zhao, Y., Brickner, J. R., Majid, M. C. & Mosammaparast, N. Crosstalk between ubiquitin and other post-translational modifications on chromatin during double-strand break repair. Trends Cell Biol. 24, 426–434 (2014).
Reichert, N., Choukrallah, M. A. & Matthias, P. Multiple roles of class I HDACs in proliferation, differentiation, and development. Cell. Mol. Life Sci. 69, 2173–2187 (2012).
Lahm, A. et al. Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases. Proc. Natl Acad. Sci. USA 104, 17335–17340 (2007).
Fischle, W. et al. Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR. Mol. Cell 9, 45–57 (2002).
Murphy, J. M., Farhan, H. & Eyers, P. A. Bio-Zombie: the rise of pseudoenzymes in biology. Biochem. Soc. Trans. 45, 537–544 (2017).
Dovey, O. M. et al. Histone deacetylase 1 and 2 are essential for normal T cell development and genomic stability in mice. Blood 121, 1335–1344 (2013).
Hagelkruys, A. et al. A single allele of Hdac2 but not Hdac1 is sufficient for normal mouse brain development in the absence of its paralog. Development 141, 604–616 (2014).
Winter, M. et al. Divergent roles of HDAC1 and HDAC2 in the regulation of epidermal development and tumorigenesis. EMBO J. 32, 3176–3191 (2013).
Sun, Z. et al. Deacetylase-independent function of HDAC3 in transcription and metabolism requires nuclear receptor corepressor. Mol. Cell 52, 769–782 (2013).
Matthias, P., Yoshida, M. & Khochbin, S. HDAC6 a new cellular stress surveillance factor. Cell Cycle 7, 7–10 (2008).
Bird, J. J. et al. Helper T cell differentiation is controlled by the cell cycle. Immunity 9, 229–237 (1998).
Valapour, M. et al. Histone deacetylation inhibits IL4 gene expression in T cells. J. Allergy Clin. Immunol. 109, 238–245 (2002).
Morinobu, A., Kanno, Y. & O’Shea, J. J. Discrete roles for histone acetylation in human T helper 1 cell-specific gene expression. J. Biol. Chem. 279, 40640–40646 (2004).
Su, R. C., Becker, A. B., Kozyrskyj, A. L. & Hayglass, K. T. Epigenetic regulation of established human type 1 versus type 2 cytokine responses. J. Allergy Clin. Immunol. 121, 57–63 (2008).
Tao, R. et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat. Med. 13, 1299–1307 (2007). This study demonstrates that HDAC inhibitor treatment in vivo increases FOXP3 expression and increases both the number and the suppressive activity of FOXP3 + T reg cells and that FOXP3 acetylation increases FOXP3 activity.
Lucas, J. L. et al. Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors. Cell. Immunol. 257, 97–104 (2009).
van Loosdregt, J. et al. Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood 115, 965–974 (2010). This study shows that modulation of the acetylation state of FOXP3 provides a novel molecular mechanism for assuring rapid temporal control of FOXP3 levels in T cells, thereby regulating T reg cell numbers and functionality.
Donas, C. et al. Trichostatin A promotes the generation and suppressive functions of regulatory T cells. Clin. Dev. Immunol. 2013, 679804 (2013).
Akimova, T., Beier, U. H., Liu, Y., Wang, L. & Hancock, W. W. Histone/protein deacetylases and T cell immune responses. Blood 119, 2443–2451 (2012).
Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019–1031 (2009). This publication describes genome-wide mapping of HATs and HDACs that bind to chromatin in human CD4 + T cells and reveals that both are found at active genes with acetylated histones, suggesting that a dynamic cycle of acetylation and deacetylation by the transient binding of HATs and HDACs, together with prior H3K4 methylation, poises the primed genes for future activation.
Heideman, M. R. et al. Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function. Blood 121, 2038–2050 (2013).
Boucheron, N. et al. CD4+ T cell lineage integrity is controlled by the histone deacetylases HDAC1 and HDAC2. Nat. Immunol. 15, 439–448 (2014). This study reveals an unexpected plasticity of CD4 + T cells towards the CD8 lineage and demonstrates that HDAC1 and HDAC2 maintain integrity of the CD4 lineage by repressing RUNX3–CBFβ complexes that otherwise induce a CD8 + effector T cell-like programme in CD4 + T cells.
Philips, R. L. et al. HDAC3 is required for the downregulation of RORgammat during thymocyte positive selection. J. Immunol. 197, 541–554 (2016).
Stengel, K. R. et al. Histone deacetylase 3 is required for efficient T cell development. Mol. Cell. Biol. 35, 3854–3865 (2015).
Kasler, H. G. et al. Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/CD8 double-positive thymocytes. J. Immunol. 186, 4782–4793 (2011).
Fink, P. J. The biology of recent thymic emigrants. Annu. Rev. Immunol. 31, 31–50 (2013).
Hsu, F. C. et al. Immature recent thymic emigrants are eliminated by complement. J. Immunol. 193, 6005–6015 (2014).
Hsu, F. C. et al. Histone deacetylase 3 is required for T cell maturation. J. Immunol. 195, 1578–1590 (2015).
Myers, D. R., Zikherman, J. & Roose, J. P. Tonic signals: why do lymphocytes bother? Trends Immunol. 38, 844–857 (2017).
Myers, D. R. et al. Tonic LAT-HDAC7 signals sustain Nur77 and Irf4 expression to tune naive CD4 T cells. Cell Rep. 19, 1558–1571 (2017).
Reis, B. S., Rogoz, A., Costa-Pinto, F. A., Taniuchi, I. & Mucida, D. Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4+ T cell immunity. Nat. Immunol. 14, 271–280 (2013).
Mucida, D. et al. Transcriptional reprogramming of mature CD4+ helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes. Nat. Immunol. 14, 281–289 (2013).
Cheroutre, H. & Husain, M. M. CD4 CTL: living up to the challenge. Semin. Immunol. 25, 273–281 (2013).
Takeuchi, A. & Saito, T. CD4 CTL, a cytotoxic subset of CD4+ T cells, their differentiation and function. Front. Immunol. 8, 194 (2017).
Juno, J. A. et al. Cytotoxic CD4 T cells-friend or foe during viral infection? Front. Immunol. 8, 19 (2017).
Zhang, M., Zhang, J., Rui, J. & Liu, X. p300-mediated acetylation stabilizes the Th-inducing POK factor. J. Immunol. 185, 3960–3969 (2010).
Jin, Y. H. et al. Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. J. Biol. Chem. 279, 29409–29417 (2004).
Rui, J., Liu, H., Zhu, X., Cui, Y. & Liu, X. Epigenetic silencing of Cd8 genes by ThPOK-mediated deacetylation during CD4 T cell differentiation. J. Immunol. 189, 1380–1390 (2012).
Walker, J. A. & McKenzie, A. N. J. TH2 cell development and function. Nat. Rev. Immunol. 18, 121–133 (2018).
DuPage, M. & Bluestone, J. A. Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease. Nat. Rev. Immunol. 16, 149–163 (2016).
Avni, O. et al. T(H) cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat. Immunol. 3, 643–651 (2002).
Fields, P. E., Kim, S. T. & Flavell, R. A. Cutting edge: changes in histone acetylation at the IL-4 and IFN-gamma loci accompany Th1/Th2 differentiation. J. Immunol. 169, 647–650 (2002). References 82 and 83 are the first studies to demonstrate that T H 1 cell and T H 2 cell differentiation are associated with dynamic changes in histone acetylation patterns at the respective cytokine loci.
Kanno, Y., Vahedi, G., Hirahara, K., Singleton, K. & O’Shea, J. J. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu. Rev. Immunol. 30, 707–731 (2012).
Grausenburger, R. et al. Conditional deletion of histone deacetylase 1 in T cells leads to enhanced airway inflammation and increased Th2 cytokine production. J. Immunol. 185, 3489–3497 (2010).
Christie, D. & Zhu, J. Transcriptional regulatory networks for CD4 T cell differentiation. Curr. Top. Microbiol. Immunol. 381, 125–172 (2014).
Yamagata, T. et al. Acetylation of GATA-3 affects T cell survival and homing to secondary lymphoid organs. EMBO J. 19, 4676–4687 (2000).
Colley, T. et al. Defective sirtuin-1 increases IL-4 expression through acetylation of GATA-3 in patients with severe asthma. J. Allergy Clin. Immunol. 137, 1595–1597 (2016).
Goschl, L. et al. A T cell-specific deletion of HDAC1 protects against experimental autoimmune encephalomyelitis. J. Autoimmun 86, 51–61 (2018). This study reveals a novel pathophysiological role for HDAC1 in EAE and provides evidence that selective inhibition of HDAC1 might be a promising strategy for the treatment of multiple sclerosis.
Klampfer, L., Huang, J., Swaby, L. A. & Augenlicht, L. Requirement of histone deacetylase activity for signaling by STAT1. J. Biol. Chem. 279, 30358–30368 (2004).
Woods, D. M. et al. T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model. Blood 130, 146–155 (2017).
Zhang, J. N. et al. The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J. Clin. Invest. 119, 3048–3058 (2009).
Beier, U. H. et al. Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival. Mol. Cell. Biol. 31, 1022–1029 (2011).
Mishra, N., Reilly, C. M., Brown, D. R., Ruiz, P. & Gilkeson, G. S. Histone deacetylase inhibitors modulate renal disease in the MRL-lpr/lpr mouse. J. Clin. Invest. 111, 539–552 (2003).
Yan, K. et al. Histone deacetylase 9 deficiency protects against effector T cell-mediated systemic autoimmunity. J. Biol. Chem. 286, 28833–28843 (2011).
Boyault, C., Sadoul, K., Pabion, M. & Khochbin, S. HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene 26, 5468–5476 (2007).
Etienne-Manneville, S. Microtubules in cell migration. Annu. Rev. Cell Dev. Biol. 29, 471–499 (2013).
Cabrero, J. R. et al. Lymphocyte chemotaxis is regulated by histone deacetylase 6, independently of its deacetylase activity. Mol. Biol. Cell 17, 3435–3445 (2006).
Josefowicz, S. Z., Lu, L. F. & Rudensky, A. Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012).
Lu, L., Barbi, J. & Pan, F. The regulation of immune tolerance by FOXP3. Nat. Rev. Immunol. 17, 703–717 (2017).
Li, B. et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc. Natl Acad. Sci. USA 104, 4571–4576 (2007). This publication reveals that FOXP3 actively mediates transcriptional repression via either a HAT-containing complex or an HDAC-containing complex.
van Loosdregt, J. et al. Rapid temporal control of Foxp3 protein degradation by sirtuin-1. PLOS One 6, e19047 (2011).
Kwon, H. S. et al. Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells. J. Immunol. 188, 2712–2721 (2012).
van Loosdregt, J. & Coffer, P. J. Post-translational modification networks regulating FOXP3 function. Trends Immunol. 35, 368–378 (2014).
Xie, X. et al. The regulatory T cell lineage factor Foxp3 regulates gene expression through several distinct mechanisms mostly independent of direct DNA binding. PLOS Genet. 11, e1005251 (2015).
Wang, L. et al. FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3. J. Clin. Invest. 125, 1111–1123 (2015).
Huang, J. et al. Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function. Sci. Rep. 7, 8626 (2017).
de Zoeten, E. F. et al. Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3+ T-regulatory cells. Mol. Cell. Biol. 31, 2066–2078 (2011).
de Zoeten, E. F., Wang, L., Sai, H., Dillmann, W. H. & Hancock, W. W. Inhibition of HDAC9 increases T regulatory cell function and prevents colitis in mice. Gastroenterology 138, 583–594 (2010).
Beier, U. H. et al. Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Sci. Signal. 5, ra45 (2012).
Malek, T. R. & Bayer, A. L. Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4, 665–674 (2004).
Xiao, H. et al. HDAC5 controls the functions of Foxp3+ T-regulatory and CD8+ T cells. Int. J. Cancer 138, 2477–2486 (2016).
Beier, U. H. et al. Essential role of mitochondrial energy metabolism in Foxp3+ T-regulatory cell function and allograft survival. FASEB J. 29, 2315–2326 (2015).
Stockinger, B. & Omenetti, S. The dichotomous nature of T helper 17 cells. Nat. Rev. Immunol. 17, 535–544 (2017).
Burkett, P. R., Meyer zu Horste, G. & Kuchroo, V. K. Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity. J. Clin. Invest. 125, 2211–2219 (2015).
Lim, H. W. et al. SIRT1 deacetylates RORgammat and enhances Th17 cell generation. J. Exp. Med. 212, 607–617 (2015). This work shows that loss of SIRT1 leads to RORγt hyperacetylation, which reduces RORγt activity, impairs T H 17 cell differentiation and reduces clinical EAE score, suggesting that SIRT1 inhibition is a therapeutic approach against autoimmunity.
Limagne, E. et al. Sirtuin-1 Activation controls tumor growth by impeding Th17 differentiation via STAT3 deacetylation. Cell Rep. 19, 746–759 (2017).
Guery, L. & Hugues, S. Th17 cell plasticity and functions in cancer immunity. Biomed. Res. Int. 2015, 314620 (2015).
Wu, Q. et al. Reciprocal regulation of RORgammat acetylation and function by p300 and HDAC1. Sci. Rep. 5, 16355 (2015).
Camelo, S. et al. Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis. J. Neuroimmunol. 164, 10–21 (2005).
Jayaraman, A., Soni, A., Prabhakar, B. S., Holterman, M. & Jayaraman, S. The epigenetic drug trichostatin A ameliorates experimental autoimmune encephalomyelitis via T cell tolerance induction and impaired influx of T cells into the spinal cord. Neurobiol. Dis. 108, 1–12 (2017).
Ge, Z. et al. Vorinostat, a histone deacetylase inhibitor, suppresses dendritic cell function and ameliorates experimental autoimmune encephalomyelitis. Exp. Neurol. 241, 56–66 (2013).
Kaplan, M. H., Hufford, M. M. & Olson, M. R. The development and in vivo function of T helper 9 cells. Nat. Rev. Immunol. 15, 295–307 (2015).
Wang, Y. et al. Histone deacetylase SIRT1 negatively regulates the differentiation of interleukin-9-producing CD4+ T cells. Immunity 44, 1337–1349 (2016). This is the first study to link an HDAC family member with the differentiation and function of T H 9 cell subsets.
Chandra, S. & Kronenberg, M. Activation and function of iNKT and MAIT cells. Adv. Immunol. 127, 145–201 (2015).
Jameson, S. C., Lee, Y. J. & Hogquist, K. A. Innate memory T cells. Adv. Immunol. 126, 173–213 (2015).
Thapa, P. et al. The transcriptional repressor NKAP is required for the development of iNKT cells. Nat. Commun. 4, 1582 (2013).
Thapa, P., Romero Arocha, S., Chung, J. Y., Sant’Angelo, D. B. & Shapiro, V. S. Histone deacetylase 3 is required for iNKT cell development. Sci. Rep. 7, 5784 (2017).
Kasler, H. G., Lee, I. S., Lim, H. W. & Verdin, E. Histone Deacetylase 7 mediates tissue-specific autoimmunity via control of innate effector function in invariant natural killer T cells. Elife 7, e32109 (2018).
Liu, Q. et al. HDAC4 is expressed on multiple T cell lineages but dispensable for their development and function. Oncotarget 8, 17562–17572 (2017).
Mihaylova, M. M. & Shaw, R. J. Metabolic reprogramming by class I and II histone deacetylases. Trends Endocrinol. Metab. 24, 48–57 (2013).
Menzies, K. J., Zhang, H., Katsyuba, E. & Auwerx, J. Protein acetylation in metabolism - metabolites and cofactors. Nat. Rev. Endocrinol. 12, 43–60 (2016).
Anderson, K. A., Madsen, A. S., Olsen, C. A. & Hirschey, M. D. Metabolic control by sirtuins and other enzymes that sense NAD+, NADH, or their ratio. Biochim. Biophys. Acta 1858, 991–998 (2017).
Kebede, A. F. et al. Histone propionylation is a mark of active chromatin. Nat. Struct. Mol. Biol. 24, 1048–1056 (2017).
Goudarzi, A. et al. Dynamic competing histone H4 K5K8 acetylation and butyrylation are hallmarks of highly active gene promoters. Mol. Cell 62, 169–180 (2016).
Li, Y. et al. Molecular coupling of histone crotonylation and active transcription by AF9 YEATS domain. Mol. Cell 62, 181–193 (2016). In this study, the authors identify the YEATS domain of the myeloid/lymphoid or mixed-lineage leukaemia (MLL) fusion partner protein AF9 as a reader domain for crotonylated histones and show that protein AF9 positively affects gene expression in a YEATS domain-dependent manner.
Jiang, G. et al. HIV latency is reversed by ACSS2-driven histone crotonylation. J. Clin. Invest. 128, 1190–1198 (2018).
Du, J. et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806–809 (2011).
Wei, W. et al. Class I histone deacetylases are major histone decrotonylases: evidence for critical and broad function of histone crotonylation in transcription. Cell Res. 27, 898–915 (2017).
Fellows, R. et al. Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases. Nat. Commun. 9, 105 (2018).
Moreno-Yruela, C., Galleano, I., Madsen, A. S. & Olsen, C. A. Histone deacetylase 11 is an ε-N-myristoyllysine hydrolase. Cell Chem. Biol. https://doi.org/10.1016/j.chembiol.2018.04.007 (2018).
Kutil, Z. et al. Histone deacetylase 11 is a fatty-acid deacylase. ACS Chem. Biol. 13, 685–693 (2018).
Cheng, Z. et al. Molecular characterization of propionyllysines in non-histone proteins. Mol. Cell Proteom. 8, 45–52 (2009).
West, A. C. & Johnstone, R. W. New and emerging HDAC inhibitors for cancer treatment. J. Clin. Invest. 124, 30–39 (2014).
Falkenberg, K. J. & Johnstone, R. W. Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders. Nat. Rev. Drug Discov. 13, 673–691 (2014).
Hu, J., Jing, H. & Lin, H. Sirtuin inhibitors as anticancer agents. Future Med. Chem. 6, 945–966 (2014).
Raedler, L. A. Farydak (panobinostat): first HDAC inhibitor approved for patients with relapsed multiple myeloma. Am. Health Drug Benefits 9, 84–87 (2016).
Moskowitz, A. J. & Horwitz, S. M. Targeting histone deacetylases in T cell lymphoma. Leuk. Lymphoma 58, 1306–1319 (2017).
Haery, L., Thompson, R. C. & Gilmore, T. D. Histone acetyltransferases and histone deacetylases in B− and T cell development, physiology and malignancy. Genes Cancer 6, 184–213 (2015).
Dinarello, C. A., Fossati, G. & Mascagni, P. Histone deacetylase inhibitors for treating a spectrum of diseases not related to cancer. Mol. Med. 17, 333–352 (2011).
Duvic, M. & Dimopoulos, M. The safety profile of vorinostat (suberoylanilide hydroxamic acid) in hematologic malignancies: a review of clinical studies. Cancer Treat. Rev. 43, 58–66 (2016).
Matalon, S., Rasmussen, T. A. & Dinarello, C. A. Histone deacetylase inhibitors for purging HIV-1 from the latent reservoir. Mol. Med. 17, 466–472 (2011).
Shirakawa, K., Chavez, L., Hakre, S., Calvanese, V. & Verdin, E. Reactivation of latent HIV by histone deacetylase inhibitors. Trends Microbiol. 21, 277–285 (2013).
Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).
Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352 (2016).
Levy, M., Kolodziejczyk, A. A., Thaiss, C. A. & Elinav, E. Dysbiosis and the immune system. Nat. Rev. Immunol. 17, 219–232 (2017).
Waldecker, M., Kautenburger, T., Daumann, H., Busch, C. & Schrenk, D. Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. J. Nutr. Biochem. 19, 587–593 (2008).
Nilsson, N. E., Kotarsky, K., Owman, C. & Olde, B. Identification of a free fatty acid receptor, FFA2R, expressed on leukocytes and activated by short-chain fatty acids. Biochem. Biophys. Res. Commun. 303, 1047–1052 (2003).
Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation. Nature 504, 451–455 (2013). References 159, 160 and 161 reveal that commensal bacteria produce metabolites, including short-chain fatty acids such as butyrate, that have HDAC inhibitor activity and, thus, these bacteria regulate colonic T reg cell homeostasis.
Hassig, C. A., Fleischer, T. C., Billin, A. N., Schreiber, S. L. & Ayer, D. E. Histone deacetylase activity is required for full transcriptional repression by mSin3A. Cell 89, 341–347 (1997).
Zhang, Y., LeRoy, G., Seelig, H. P., Lane, W. S. & Reinberg, D. The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 95, 279–289 (1998).
Wade, P. A., Jones, P. L., Vermaak, D. & Wolffe, A. P. A multiple subunit Mi-2 histone deacetylase from Xenopus laevis cofractionates with an associated Snf2 superfamily ATPase. Curr. Biol. 8, 843–846 (1998).
Tong, J. K., Hassig, C. A., Schnitzler, G. R., Kingston, R. E. & Schreiber, S. L. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395, 917–921 (1998).
Xue, Y. et al. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol. Cell 2, 851–861 (1998).
Bantscheff, M. et al. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. Nat. Biotechnol. 29, 255–265 (2011).
Choi, E. et al. A novel germ cell-specific protein, SHIP1, forms a complex with chromatin remodeling activity during spermatogenesis. J. Biol. Chem. 283, 35283–35294 (2008).
Liang, J. et al. Nanog and Oct4 associate with unique transcriptional repression complexes in embryonic stem cells. Nat. Cell Biol. 10, 731–739 (2008).
Li, J. et al. Both corepressor proteins SMRT and N-CoR exist in large protein complexes containing HDAC3. EMBO J. 19, 4342–4350 (2000).
Yang, X. J. & Gregoire, S. Class II histone deacetylases: from sequence to function, regulation, and clinical implication. Mol. Cell. Biol. 25, 2873–2884 (2005).
Parra, M. & Verdin, E. Regulatory signal transduction pathways for class IIa histone deacetylases. Curr. Opin. Pharmacol. 10, 454–460 (2010).
Kawaguchi, Y. et al. The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 115, 727–738 (2003).
Hai, Y., Shinsky, S. A., Porter, N. J. & Christianson, D. W. Histone deacetylase 10 structure and molecular function as a polyamine deacetylase. Nat. Commun. 8, 15368 (2017).
Verdel, A. & Khochbin, S. Identification of a new family of higher eukaryotic histone deacetylases. Coordinate expression of differentiation-dependent chromatin modifiers. J. Biol. Chem. 274, 2440–2445 (1999).
Houtkooper, R. H., Pirinen, E. & Auwerx, J. Sirtuins as regulators of metabolism and healthspan. Nat. Rev. Mol. Cell Biol. 13, 225–238 (2012).
Gao, L., Cueto, M. A., Asselbergs, F. & Atadja, P. Cloning and functional characterization of HDAC11, a novel member of the human histone deacetylase family. J. Biol. Chem. 277, 25748–25755 (2002).
Thiagarajan, D., Vedantham, S., Ananthakrishnan, R., Schmidt, A. M. & Ramasamy, R. Mechanisms of transcription factor acetylation and consequences in hearts. Biochim. Biophys. Acta 1862, 2221–2231 (2016).
Park, J. M., Jo, S. H., Kim, M. Y., Kim, T. H. & Ahn, Y. H. Role of transcription factor acetylation in the regulation of metabolic homeostasis. Protein Cell 6, 804–813 (2015).
van den Bosch, T., Kwiatkowski, M., Bischoff, R. & Dekker, F. J. Targeting transcription factor lysine acetylation in inflammatory airway diseases. Epigenomics 9, 1013–1028 (2017).
Hu, X., Yu, Y., Eugene Chin, Y. & Xia, Q. The role of acetylation in TLR4-mediated innate immune responses. Immunol. Cell Biol. 91, 611–614 (2013).
Wang, D. et al. Acetylation-regulated interaction between p53 and SET reveals a widespread regulatory mode. Nature 538, 118–122 (2016).
Schwer, B., Bunkenborg, J., Verdin, R. O., Andersen, J. S. & Verdin, E. Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl Acad. Sci. USA 103, 10224–10229 (2006).
Hallows, W. C., Lee, S. & Denu, J. M. Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl Acad. Sci. USA 103, 10230–10235 (2006).
Li, T., Diner, B. A., Chen, J. & Cristea, I. M. Acetylation modulates cellular distribution and DNA sensing ability of interferon-inducible protein IFI16. Proc. Natl Acad. Sci. USA 109, 10558–10563 (2012).
Tschismarov, R. et al. HDAC1 controls CD8+ T cell homeostasis and antiviral response. PLOS ONE 9, e110576 (2014).
Nunez-Andrade, N. et al. HDAC6 regulates the dynamics of lytic granules in cytotoxic T lymphocytes. J. Cell Sci. 129, 1305–1311 (2016).
Jeng, M. Y. et al. Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1. J. Exp. Med. 215, 51–62 (2018).
Yan, B. et al. HDAC6 regulates IL-17 expression in T lymphocytes: implications for HDAC6-targeted therapies. Theranostics 7, 1002–1009 (2017).
Kasler, H. G. et al. Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance. EMBO J. 31, 4453–4465 (2012).
Ciarlo, E. et al. Sirtuin 3 deficiency does not alter host defenses against bacterial and fungal infections. Sci. Rep. 7, 3853 (2017).
The authors apologize to those colleagues whose work could not be cited owing to space limitations. Within the past few years, the work in the laboratory of W.E. has been funded by the Austrian Science Fund (P14261, P16708, P19930, P23641, P26193, P29790, I00698, Y163 and SFB F23), the European Union (EU) Horizon 2020 Marie Sklodowska Curie programme (grant agreement 675395) and the Austrian Science Fund–MedUni Wien PhD programme Inflammation and Immunity (W1212). The work in the laboratory of C.S. has been funded by the Austrian Science Fund (P28705, P28034, P26193, P25807, P16443, P14909, P13638 and P13068) and the Austrian Science Fund PhD programmes W1220 and W1261. W.E. and C.S. were also funded by a joint grant of the Vienna Science and Technology Fund (WWTF) through project LS09-031.
Nature Reviews Immunology thanks W. Hancock and the other anonymous reviewer(s) for their assistance with the peer review of this manuscript.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The basic structural subunit of chromatin, which consists of ~147 bp DNA wrapped around an octamer of histones.
- ε-Amino group
The functional group of the amino acid lysine, which is frequently targeted by modifications including acetylation and other acylations, methylation, ubiquitylation and sumoylation. The ε-amino group is positively charged, but it loses its charge upon acetylation.
- Histone code
A regulatory system allowing the control of chromatin accessibility and expression of genes by combinations of post-translational histone modifications including acetylation, methylation, phosphorylation, ubiquitylation, methylation, sumoylation and ADP-ribosylation. These modifications serve as docking sites for reader proteins, leading to the recruitment of protein complexes that alter chromatin structure and thus the transcription of target genes.
- Epigenetic readers
Proteins that recognize and bind specifically to modified histones and other modified proteins. These proteins usually have specific domains such as bromodomains for reading acetylation marks or chromodomains for reading methylation marks. Alternatively, certain readers specifically bind to histone tails only in the absence of the modification.
Protein domains that are ~70–110 amino acids in length and that recognize lysine acetylation marks on histone proteins. Bromodomains are present in some histone acetyltransferases and are also found in factors that recruit either chromatin remodelling complexes to target sites or basal transcription factors to gene promoters.
- YEATS domains
Named after their five founding domain-containing proteins (YAF9, ENL, AF9, TAF14 and SAS5), these protein domains are ~80 amino acids in length and recognize lysine acetylation or crotonylation marks on histones.
- Plant homeodomain
(PHD). A protein domain that is ~50–80 amino acids in length and that recognizes lysine methylation and lysine acetylation marks. PHDs are present in reader proteins, which include the histone acetyltransferase p300 and CREB-binding protein (CBP).
- Epigenetic writers
Enzymes such as histone acetyltransferases and histone methyltransferases that add post-translational modifications on histones.
- Epigenetic erasers
Enzymes that remove histone modifications. This group of proteins includes histone deacetylases and histone demethylases.
- NCOR1–SMRT co-repressor
A complex formed by two factors (nuclear receptor co-repressor 1 (NCOR1) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT)) that are transcriptional co-repressors; the complex bridges gene-specific transcription factors, such as nuclear receptors or members of the BTB domain zinc-finger transcription family, with chromatin modifying enzymes. Histone deacetylase 3 (HDAC3) is the major HDAC member recruited by NCOR1 complexes.
- SWI/SNF complex
(Switch/sucrose non-fermentable complex). A highly conserved multiprotein complex with ATPase activity. The SWI/SNF complex, which is also known as the BRG1/BRM associated factor (BAF) complex has chromatin remodelling function, that is, it changes the accessibility of specific chromatin regions by moving, ejecting or restructuring nucleosomes.
- Tonic signalling
Low-level, constitutive antigen receptor signalling in B and T cells in the basal state. This signalling is essential for the survival of B cells and the maintenance of peripheral T cell fitness. It is also implicated in maintaining T cell tolerance.
- Experimental autoimmune encephalomyelitis
(EAE). An (auto)inflammatory disease in mice induced by injecting myelin basic protein or peptides derived from myelin oligodendrocyte glycoprotein or proteolipid protein together with complete Freund’s adjuvant and pertussis toxin. EAE is characterized by paralysis and inflammation and demyelination in the central nervous system and is a model of human multiple sclerosis.
- Invariant natural killer T cells
(iNKT cells). A subset of natural killer T (NKT) cells that express a T cell receptor (TCR) with an invariant Vα14–Jα18 (in mice) or Vα24–Jα18 (in humans) TCR α-chain paired with a restricted subset of TCR Vβ chains. iNKT cells exclusively recognize glycolipid antigens that are presented on CD1d molecules and rapidly produce cytokines after activation.
About this article
Cite this article
Ellmeier, W., Seiser, C. Histone deacetylase function in CD4+ T cells. Nat Rev Immunol 18, 617–634 (2018). https://doi.org/10.1038/s41577-018-0037-z
Design, synthesis and biological evaluation of novel HDAC inhibitors with improved pharmacokinetic profile in breast cancer
European Journal of Medicinal Chemistry (2020)
HDAC6 is critical for ketamine-induced impairment of dendritic and spine growth in GABAergic projection neurons
Acta Pharmacologica Sinica (2020)
Strengthening epithelial barriers through modulation of the histone code in allergic diseases—a novel approach for preventing the atopic march?
Journal of Allergy and Clinical Immunology (2020)
Journal of Medicinal Chemistry (2020)
Journal of Neurochemistry (2020)