HDAC3 Is Required for the Downregulation of RORγt during Thymocyte Positive Selection

Philips, Rachael Laura; Chen, Meibo W.; McWilliams, Douglas C.; Belmonte, Paul; Constans, Megan; Shapiro, Virginia Smith

doi:10.4049/jimmunol.1502529

Cited by 28 publications

(47 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ChIP assays revealed that HDAC3 directly deacetylates histones to inhibit RORγt gene expression. The deletion of RORγt and transgenic expression of Bcl-xl corrects the positive selection defect in HDAC3-cKO mice [86]. HDAC3 is also required for T cell development from DN stage 4 into the early CD4/CD8 DP stage.…”

Section: T Cellmentioning

confidence: 98%

Role of HDACs in normal and malignant hematopoiesis

2020

View full text Add to dashboard Cite

Normal hematopoiesis requires the accurate orchestration of lineage-specific patterns of gene expression at each stage of development, and epigenetic regulators play a vital role. Disordered epigenetic regulation has emerged as a key mechanism contributing to hematological malignancies. Histone deacetylases (HDACs) are a series of key transcriptional cofactors that regulate gene expression by deacetylation of lysine residues on histone and nonhistone proteins. In normal hematopoiesis, HDACs are widely involved in the development of various lineages. Their functions involve stemness maintenance, lineage commitment determination, cell differentiation and proliferation, etc. Deregulation of HDACs by abnormal expression or activity and oncogenic HDAC-containing transcriptional complexes are involved in hematological malignancies. Currently, HDAC family members are attractive targets for drug design, and a variety of HDAC-based combination strategies have been developed for the treatment of hematological malignancies. Drug resistance and limited therapeutic efficacy are key issues that hinder the clinical applications of HDAC inhibitors (HDACis). In this review, we summarize the current knowledge of how HDACs and HDAC-containing complexes function in normal hematopoiesis and highlight the etiology of HDACs in hematological malignancies. Moreover, the implication and drug resistance of HDACis are also discussed. This review presents an overview of the physiology and pathology of HDACs in the blood system.

show abstract

Section: T Cellmentioning

confidence: 98%

Role of HDACs in normal and malignant hematopoiesis

2020

View full text Add to dashboard Cite

show abstract

“…RORgT is a crucial TF involved in the development of Th17 lymphocytes from naive CD4 + cells [7], and although its regulation at the transcription level in mouse models and in humans is well understood [3,21,31,32], how the gene is regulated epigenetically remains elusive. There is increasing evidence that various HDACs are involved [29,30], although treatments with HDAC inhibitors have led to different, sometimes conflicting, results [29,[45][46][47][48]. In this report, we investigated how HDAC inhibitors influence human RORgT expression in 3 cellular models: primary CD4 + cells differentiating toward Th17 cells, differentiated Th17 lymphocytes, and the Jurkat T cell line.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of HDAC activity in the regulation of the Rorgt gene was recently demonstrated using conditional knockout mice: Hdac3 was shown to be necessary for the inhibition of Rorgt gene expression during thymocyte-positive selection [30]. Using TNF-a inhibitors, as well as anacardic acid (an acetyltransferase inhibitor), Lin et al [34] were able to down-regulate Rorgt expression in a process associated with a decrease in histone acetylation in its promoter.…”

Section: Discussionmentioning

confidence: 99%

“…Most knowledge regarding the mechanisms regulating the expression of RORgT has come from mouse model studies, which have revealed the involvement of several TFs acting as positive or negative regulators of the gene, e.g., STAT3, IRF4, c-Rel, Id1, E2A, HEB, Sox5, c-Maf, TCF1, and ER [21][22][23][24][25][26][27][28][29], as well as epigenetic pathways linked to HDACs [29], [30]. The 59 proximal region of human RORgT contains 4 conserved E-boxes capable of binding USF TFs [3] and 2 primate-specific GC-boxes that are indispensable for promoter activity and are occupied by the TFs Sp1 and Sp2 [31,32].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differentiation stage-specific effect of histone deacetylase inhibitors on the expression of RORγT in human lymphocytes

Sałkowska

Karaś

Walczak‐Drzewiecka

et al. 2017

Journal of Leukocyte Biology

View full text Add to dashboard Cite

The role of epigenetic mechanisms in the regulation of the human gene, which encodes a Th17 lymphocyte signature transcription factor, remains largely unknown. We investigated the effect of histone deacetylase (HDAC) inhibition on RORγT and RORγT-dependent gene expression in human T lymphocytes. We found that, in Jurkat T cells and in in vitro-differentiated Th17 cells, treatment with 2 HDAC inhibitors, butyrate and apicidin, led to the induction of the gene, which was associated with an increase in histone H4 acetylation near the proximal promoter. In contrast, when the same inhibitors were added to naive CD4 cells differentiating in vitro to Th17 cells, they mediated the down-regulation of expression. In conclusion, HDAC inhibitor-mediated H4 acetylation is involved in the epigenetic regulation of expression in Th17 cells. However, that epigenetic mechanism was observed only at a specific stage of T cell differentiation, suggesting a complex interaction with additional mechanisms that sequentially regulate expression. These observations may be relevant to the development of applications for HDAC inhibitors for diseases in which Th17 cells have a role in pathogenic mechanisms, such as some types of cancer or autoimmunologic disorders, to prevent unwanted side effects.

show abstract

“…Because HDAC3 is the main HDAC member associated with NCOR1 corepressor complexes, one might expect that loss of HDAC3 in T cells leads to similar phenotypes. Indeed, several studies showed that HDAC3 is an important regulator of T cell development as well as of T reg cell functions . Early deletion of HDAC3 in common lymphoid progenitor cells (CLPs) using the Cd2 ‐iCre transgene (HDAC3‐cKO iCd2 ) or in DN thymocytes using the Lck ‐Cre deleter strain (HDAC3‐cKO Lck ) leads to a developmental block at the DP stage due to a defect in positive selection, which is reminiscent of the developmental alterations observed in NCOR1‐cKO Lck and NCOR1‐cKO Cd4 mice.…”

Section: T Cell Development In the Absence Of Ncor1 Or Hdac3—similar mentioning

confidence: 99%

NCOR1—a new player on the field of T cell development

Müller

Hainberger

Stolz

et al. 2018

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Nuclear receptor corepressor 1 (NCOR1) is a transcriptional corepressor that links chromatin-modifying enzymes with gene-specific transcription factors. Although identified more than 20 years ago as a corepressor of nuclear receptors, the role of NCOR1 in T cells remained only poorly understood. However, recent studies indicate that the survival of developing thymocytes is regulated by NCOR1, revealing an essential role for NCOR1 in the T cell lineage. In this review, we will briefly summarize basic facts about NCOR1 structure and functions. We will further summarize studies demonstrating an essential role for NCOR1 in controlling positive and negative selection of thymocytes during T cell development. Finally, we will discuss similarities and differences between the phenotypes of mice with a T cell-specific deletion of NCOR1 or histone deacetylase 3 (HDAC3), because HDAC3 is the predominant member of the HDAC family that interacts with NCOR1 corepressor complexes. With this review we aim to introduce NCOR1 as a new player in the team of transcriptional coregulators that control T cell development and thus the generation of the peripheral T cell pool.

show abstract

HDAC3 Is Required for the Downregulation of RORγt during Thymocyte Positive Selection

Cited by 28 publications

References 54 publications

Role of HDACs in normal and malignant hematopoiesis

Role of HDACs in normal and malignant hematopoiesis

Differentiation stage-specific effect of histone deacetylase inhibitors on the expression of RORγT in human lymphocytes

NCOR1—a new player on the field of T cell development

Contact Info

Product

Resources

About