Conditional Deletion of Histone Deacetylase 1 in T Cells Leads to Enhanced Airway Inflammation and Increased Th2 Cytokine Production

Grausenburger, Reinhard; Bilić, Ivan; Boucheron, Nicole; Zupkovitz, Gordin; El-Housseiny, Lamia; Tschismarov, Roland; Zhang, Yu; Rembold, Martina; Gaisberger, Martin; Hartl, Arnulf; Epstein, Michelle M.; Matthias, Patrick; Seiser, Christian; Ellmeier, Wilfried

doi:10.4049/jimmunol.0903610

Cited by 122 publications

(124 citation statements)

References 46 publications

(66 reference statements)

Supporting

Mentioning

121

Contrasting

Order By: Relevance

“…These 2 studies clearly implicate HDAC1/2 in T-cell development. However, deletion of Hdac1 alone at the double positive stage of development produced a relatively mild phenotype 28 ; suggesting that, as in many other tissue systems, deletion of both Hdac1 and Hdac2 is required to observe a more substantial phenotypic effect. [1][2][3] We demonstrate here that double knock-out of Hdac1/2 results in a substantial block in T-cell development with a dramatic reduction in thymocyte cellularity and a failure to undergo the DN to DP transition.…”

Section: Introductionmentioning

confidence: 94%

Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice

Dovey

Foster

Conte

et al. 2013

Blood

128

113

View full text Add to dashboard Cite

Key Points• We demonstrate a critical role for histone deacetylase 1 and 2 (HDAC1/2) in T-cell development and the maintenance of genomic stability. IntroductionHistone deacetylase (HDAC) 1 and 2 are sister proteins (ϳ 80% identical), functionally redundant in many cell types, 1-3 which are recruited together into 3 main transcriptional complexes: Sin3A, 4 NuRD 5,6 and CoREST. 7,8 Classically, HDAC1 and 2 (HDAC1/2) function has been viewed in the context of transcriptional repression, because deacetylation of histone tails results in the tightening of nucleosomal arrays. 9,10 However, genome-wide mapping of HDAC1 (or Rpd3) binding sites in human cells 11 and yeast, 12 reveals a positive correlation with gene activity, suggesting a role for HDACs in the cyclical acetylation of histones within the vicinity of active promoters. 13 HDAC1/2 may thus have roles in both gene activation and repression.In the clinic, the HDAC inhibitor SAHA is used to treat patients with cutaneous T-cell lymphoma. 14 Therefore a greater understanding of the key pathways regulated by HDAC1/2 activity in T-lymphocyte development will help inform their use as drug targets. Moreover, as a dispensable cell type in a standard pathogen free environment, it is an excellent model to study essential genes, such as HDAC1/2. T-cell development, from immature double negative (DN), to double positive (DP) intermediates and mature (but naive) CD4 single positive (CD4SP, helper) and CD8 single positive (CD8SP, cytotoxic) populations is regulated by a number of transcription factors and chromatin modifying complexes. 15,16 Runx1 and Runx3 have nonredundant roles in the regulation of CD4 expression. [17][18][19] The zinc-finger transcriptional regulator, Gata3, is crucial for the development of the earliest T-cell progenitors. 20 ThPOK expression is necessary to direct CD4 expression in MHC II restricted cells and is also sufficient to redirect class-I MHC T cells into the CD4 T-helper lineage. 21 Individual HDACs have also been implicated in T-lymphocyte function. HDAC7 regulates cell survival and TCR signaling in DP thymocytes, 22 HDAC6 and HDAC9 regulate the activity of T-regulatory cells, 23,24 while HDAC11 directly controls IL-10 expression levels in antigen presenting cells. 25 Deletion of either Sin3A 26 or Mi2␤, 27 central components of the HDAC1/2 containing Sin3A and NuRD complexes, respectively, perturbs thymopoiesis. Loss of Sin3A causes a deficiency in the DN to DP transition and a significant reduction in the number of CD8SP cells. Mi2␤ also plays a role in DN to DP transition, and in addition is required for transcriptional activation of the Cd4 gene. These 2 studies clearly implicate HDAC1/2 in T-cell development. However, deletion of Hdac1 alone at the double positive stage of development produced a relatively mild phenotype 28 ; suggesting that, as in many other tissue systems, deletion of both Hdac1 and For personal use only. on May 9, 2018. by guest www.bloodjournal.org From Hdac2 is required to observe a more substantial phenotypic...

show abstract

Section: Introductionmentioning

confidence: 94%

Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice

Dovey

Foster

Conte

et al. 2013

Blood

128

113

View full text Add to dashboard Cite

show abstract

“…In particular, HDI treatment has been associated with neurological, cardiac, and a number of blood-related toxicities (14,15,92,96). Gene-specific and tissue-specific mouse models have begun to shed light onto which HDACs may be responsible for both the efficacy and the toxicities associated with broad-spectrum HDAC inhibition (21,36,39,52,53,63,81,95,119,132) (Table 1). In addition, while clinical trials are currently underway to determine the effectiveness of HDIs in the treatment of a number of tumor types, hematologic malignancies remain the only cancers for which these drugs have obtained FDA approval (94).…”

Section: Hdis Alter Gene Expression But Is It Important?mentioning

confidence: 99%

Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy

Stengel

Hiebert

2015

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: The contribution of epigenetic alterations to cancer development and progression is becoming increasingly clear, prompting the development of epigenetic therapies. Histone deacetylase inhibitors (HDIs) represent one of the first classes of such therapy. Two HDIs, Vorinostat and Romidepsin, are broad-spectrum inhibitors that target multiple histone deacetylases (HDACs) and are FDA approved for the treatment of cutaneous T-cell lymphoma. However, the mechanism of action and the basis for the cancer-selective effects of these inhibitors are still unclear. Recent Advances: While the anti-tumor effects of HDIs have traditionally been attributed to their ability to modify gene expression after the accumulation of histone acetylation, recent studies have identified the effects of HDACs on DNA replication, DNA repair, and genome stability. In addition, the HDIs available in the clinic target multiple HDACs, making it difficult to assign either their anti-tumor effects or their associated toxicities to the inhibition of a single protein. However, recent studies in mouse models provide insights into the tissue-specific functions of individual HDACs and their involvement in mediating the effects of HDI therapy. Critical Issues: Here, we describe how altered replication contributes to the efficacy of HDAC-targeted therapies as well as discuss what knowledge mouse models have provided to our understanding of the specific functions of class I HDACs, their potential involvement in tumorigenesis, and how their disruption may contribute to toxicities associated with HDI treatment. Future Directions: Impairment of DNA replication by HDIs has important therapeutic implications. Future studies should assess how best to exploit these findings for therapeutic gain. Antioxid. Redox Signal. 23, 51-65.

show abstract

“…The reduction of HDAC2 results from post-translational modification, such as tyrosine nitration (15). Conditional deletion of HDAC1 in T cells enhances Th2 cytokine expression in airway inflammation (16). Trichostatin A (TSA), an inhibitor of HDAC(s), attenuates airway inflammation in a mouse asthma model by decreasing expression of Th2 cytokines (17).…”

mentioning

confidence: 99%

Histone Deacetylase 3 Mediates Allergic Skin Inflammation by Regulating Expression of MCP1 Protein

Kim¹,

Kim²,

Park³

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

Conditional Deletion of Histone Deacetylase 1 in T Cells Leads to Enhanced Airway Inflammation and Increased Th2 Cytokine Production

Cited by 122 publications

References 46 publications

Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice

Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice

Class I HDACs Affect DNA Replication, Repair, and Chromatin Structure: Implications for Cancer Therapy

Histone Deacetylase 3 Mediates Allergic Skin Inflammation by Regulating Expression of MCP1 Protein

Contact Info

Product

Resources

About