The transcriptional repressor NKAP is required for the development of iNKT cells

Thapa, Puspa; Das, Joy; McWilliams, Douglas C.; Shapiro, Michael J.; Sundsbak, Rhianna S.; Nelson-Holte, Molly; Tangen, Sarah; Anderson, J. Simon; Desiderio, Stephen; Hiebert, Scott W.; Sant’Angelo, Derek B.; Shapiro, Virginia Smith

doi:10.1038/ncomms2580

Cited by 49 publications

(51 citation statements)

References 44 publications

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“…Such ongoing activation of NF-κB target genes likely contributes to the broad increase in production of Il2, Il6, and additional proinflammatory cytokines ( Figure 9C), chemokines ( Figure 9D), and chemokine and adhesion-related receptors ( Figure 9E and Supplemental Figure 11 The lethal autoimmunity induced by Treg-specific deletion of Hdac3 was unexpected. While global deletion of Hdac3 during gestation is known to cause lethality by E9.5 (35), during the course of our work, CD4-Cre-mediated deletion of Hdac3 in all T cells was reported (40). In this study, the group did not find any alterations in conventional T cell development in their CD4-Cre Hdac3 conditionally deleted mice, though the mice failed to generate invariant NKT (iNKT) cells.…”

Section: Discussionmentioning

confidence: 54%

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

Wang¹,

Liu²,

Han³

et al. 2015

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 54%

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

Wang¹,

Liu²,

Han³

et al. 2015

J. Clin. Invest.

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“…Their work contrasts with a report of Hdac3 deletion driven by CD4-Cre that caused Hdac3 deletion in all T cells 9 . Conventional T cell development was normal in CD4-Cre HDAC3 conditional knockout mice, but these mice failed to develop invariant NKT cells.…”

Section: Foxp3contrasting

confidence: 45%

Histone/protein deacetylase 3 dictates critical aspects of regulatory T cell development and function

Singer

D’Alessio

2015

Cell Mol Immunol

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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: 91%

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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The transcriptional repressor NKAP is required for the development of iNKT cells

Cited by 49 publications

References 44 publications

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

Histone/protein deacetylase 3 dictates critical aspects of regulatory T cell development and function

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

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