Histone Deacetylase 3 Is Required for Efficient T Cell Development

Stengel, Kristy R.; Zhao, Yue; Klus, Nicholas J.; Kaiser, Jonathan F.; Gordy, Laura E.; Joyce, Sebastian; Hiebert, Scott W.; Summers, Alyssa R.

doi:10.1128/mcb.00706-15

Cited by 45 publications

(49 citation statements)

References 58 publications

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“…However various aspects are different from our work, including that the block in positive selection was due to a defect in gene regulation that could be bypassed by a strong TCR signaling with an OT-II TCR transgene (51). Differences observed between both studies may stem from the mouse models utilized, where Stengal et al used an Lck-cre for HDAC3 elimination compared to CD2-icre in our work.…”

Section: Discussioncontrasting

confidence: 72%

“…However, we demonstrate that the key gene downstream of HDAC3 required for positive selection is RORγt, as protein levels were not reduced with positive selection and CD8SP thymocyte development was restored to WT levels in RB3 mice. RORC mRNA levels were also increased in DP thymocytes from Lck-cre HDAC3-cKO mice examined by Stengel et al (51). As few CD4SP thymocytes developed in RB3 mice, HDAC3 might play an additional role in thymocyte development during CD4-lineage choice.…”

Section: Discussionmentioning

confidence: 78%

“…A recent study by Stengel et al also found that HDAC3 was required for thymocyte positive selection (51). However various aspects are different from our work, including that the block in positive selection was due to a defect in gene regulation that could be bypassed by a strong TCR signaling with an OT-II TCR transgene (51).…”

Section: Discussionmentioning

confidence: 94%

“…Current and previous work demonstrates HDAC3 to be required for multiple stages in T cell development, including positive selection, peripheral T cell maturation and the generation or regulatory T cells (9, 11, 51). Utilizing different mouse models that delete HDAC3 at different stages in development (CD2-icre versus CD4-cre, Supplemental Figure 1), we have shown HDAC3 to be required for thymocyte positive selection and peripheral T cell maturation (9).…”

Section: Discussionmentioning

confidence: 99%

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

Philips

Chen

McWilliams

et al. 2016

The Journal of Immunology

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To generate functional peripheral T cells, proper gene regulation during T cell development is critical. Here, we found that histone deacetylase 3 (HDAC3) is required for T cell development. T cell development in CD2-icre HDAC3 conditional knockout mice (HDAC3-cKO) was blocked at positive selection, resulting in few CD4 and CD8 T cells, and could not be rescued by a TCR-transgene. These SP thymocytes failed to upregulate Bcl-2, leading to increased apoptosis. HDAC3-cKO mice failed to downregulate RORγt during positive selection, and phenocopied the block in positive selection in RORγt-transgenic mice. In the absence of HDAC3, the RORC promoter was hyperacetylated. In the periphery, the few CD4 T cells present were skewed towards RORγt+ IL-17-producing Th17 cells, leading to inflammatory bowel disease. Positive selection of CD8SP thymocytes was restored in RORγt-KO Bcl-xl-transgenic HDAC3-cKO mice, demonstrating that HDAC3 is required at positive selection to down-regulate RORγt.

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Section: Discussioncontrasting

confidence: 72%

Section: Discussionmentioning

confidence: 78%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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

Philips

Chen

McWilliams

et al. 2016

The Journal of Immunology

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“…However, there were also defects in the formation of the earliest lymphoid-primed multipotent progenitor cells, suggesting a more complex mechanism underlying the role of Hdac3 in lymphoid development (10). Deletion of Hdac3 in early T cells also caused a lack of cell survival and impaired differentiation, but deletion later in development caused only functional defects (37)(38)(39). Here, deletion of Hdac3 in early committed B progenitor cells uncovered unexpected roles for Hdac3 in yielding productive VDJ recombination.…”

Section: Discussionmentioning

confidence: 86%

Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development

Stengel

Barnett

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Histone deacetylase 3 (HDAC3) is the catalytic component of NCoR/SMRT corepressor complexes that mediate the actions of transcription factors implicated in the regulation of B-cell development and function. We crossed Hdac3 conditional knockout mice with Mb1-Cre knockin animals to delete Hdac3 in early progenitor B cells. The spleens of Hdac3 CD43+ populations identified a defect in V H DJ H recombination with a severe reduction in productive rearrangements, which directly corresponded to the loss of pre-B cells from Hdac3 Δ/− bone marrow. For Hdac3 Δ/− B cells that did show productive VDJ rearrangement, there was significant skewing toward the incorporation of proximal V H gene segments and a corresponding reduction in distal V H gene segment use. Although transcriptional effects within these loci were modest, Hdac3 Δ/− progenitor cells displayed global changes in chromatin structure that likely hindered effective distal V-DJ recombination. Reintroduction of wild-type Hdac3 restored normal B-cell development, whereas an Hdac3 point mutant lacking deacetylase activity failed to complement this defect. Thus, the deacetylase activity of Hdac3 is required for the generation of mature B cells.istone deacetylase 3 (Hdac3) functions as the catalytic component of NCoR/SMRT corepressor complexes that are recruited by sequence-specific transcription factors to regulate transcription through the deacetylation of both histone and nonhistone proteins (1-3). Although bulk histone acetylation is generally controlled during replication by Hdac1 and Hdac2 (4, 5), Hdac3 is required for the maintenance of heterochromatin in some tissues (6, 7). Furthermore, the ability of Hdac3 to modulate chromatin accessibility has profound effects on gene transcription, DNA replication, and DNA repair (8-13). For example, hepatocyte-specific deletion of Hdac3 resulted in global changes in histone acetylation, nucleosomal compaction, and changes in gene expression (6). Although Hdac3 has robust deacetylase activity and is proposed to mediate the activity of some class II HDACs that lack intrinsic deacetylase function (14, 15), deacetylase inactive mutants of Hdac3 appeared to partially complement the phenotype of hepatocyte-specific Hdac3-knockout mice (16). This was interesting given that the livers of Albumin-Cre-Hdac3 −/− mice displayed phenotypes associated with global increases in histone acetylation, including a loss of heterochromatin (6, 9).The adaptive immune system has provided an excellent model for the study of higher-order chromatin structure and also provides a simple genetic system in which to dissect mechanisms of action for Hdac3. Lymphocytes rely on a series of recombinationdependent genome-editing processes, such as VDJ recombination and class-switch recombination, for their development and function. These recombination events are regulated through locus accessibility and require long-range chromatin interactions (17, 18). The Rag1 and Rag2 recombinases introduce DNA doublestrand breaks at recombination signal sequences, fol...

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Epigenetics of Aberrant Cardiac Wound Healing

Russell‐Hallinan

Watson

Baugh

2018

Comprehensive Physiology

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Remodeling of cardiac tissue architecture is essential for normal organ development and maintaining homeostasis after injury. Injurious insults to the heart, such as hypertension and myocardial infarction, promote cellular responses including stimulation of resident inflammatory cells, activation of endothelial cells and recruitment of immune cells, hypertrophy of cardiomyocytes, and activation of fibroblasts. The physiological goal of this coordinated cellular response is to repair damaged tissue while maintaining or restoring cardiac contractile function. Persistent uncontrolled inflammation, hypertrophy, and fibrosis in the heart due to hyperactive wound healing are detrimental and impair cardiac performance, facilitating the progression to heart failure. Abnormal changes in gene expression promote acquisition of aberrant cellular phenotypes that drive cardiac remodeling. DNA methylation and histone modifications are epigenetic mechanisms that critically regulate chromatin structure and gene expression, and are essential for normal physiology and development. Increasing clinical and experimental evidence suggests that these epigenetic mechanisms are involved in driving aberrant wound healing and the development of heart failure. While most of our knowledge to date is on the heart as a whole, the precise contribution of DNA methylation and histone modifications in regulating aberrant cardiac remodeling at the cellular level is less defined. Therefore, this overview aims to summarize the role of DNA methylation and histone modifications (acetylation and methylation) in heart failure and to comprehensively dissect the role these mechanisms play in regulating the function of cardiomyocytes, fibroblasts, and immune cells in response to injury. © 2018 American Physiological Society. Compr Physiol 8:451-491, 2018.

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Histone Deacetylase 3 Is Required for Efficient T Cell Development

Cited by 45 publications

References 58 publications

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

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

Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development

Epigenetics of Aberrant Cardiac Wound Healing

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