BCL11B is a general transcriptional repressor of the HIV-1 long terminal repeat in T lymphocytes through recruitment of the NuRD complex

Cismasiu, Valeriu B.; Paskaleva, Elena E.; Daya, Sneha Suman; Canki, Mario; Duus, Karen; Avram, Dorina

doi:10.1016/j.virol.2008.07.035

Cited by 46 publications

(39 citation statements)

References 59 publications

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“…Depletion of CHD3 resulted in derepression of latent HIV LTR activity as measured by an increase in GFP expression (Fig 1B). In support of this observation, the CHD3 containing NuRD complex as well as the methyl CpG binding protein MBD2, which is another component of the NuRD complex, were shown to be involved in LTR repression [47,48]. The related CHD1 protein was also shown to repress the HIV LTR [49].…”

Section: Resultsmentioning

confidence: 98%

Repressive LTR Nucleosome Positioning by the BAF Complex Is Required for HIV Latency

et al. 2011

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Persistence of a reservoir of latently infected memory T cells provides a barrier to HIV eradication in treated patients. Several reports have implicated the involvement of SWI/SNF chromatin remodeling complexes in restricting early steps in HIV infection, in coupling the processes of integration and remodeling, and in promoter/LTR transcription activation and repression. However, the mechanism behind the seemingly contradictory involvement of SWI/SNF in the HIV life cycle remains unclear. Here we addressed the role of SWI/SNF in regulation of the latent HIV LTR before and after transcriptional activation. We determined the predicted nucleosome affinity of the LTR sequence and found a striking reverse correlation when compared to the strictly positioned in vivo LTR nucleosomal structure; sequences encompassing the DNase hypersensitive regions displayed the highest nucleosome affinity, while the strictly positioned nucleosomes displayed lower affinity for nucleosome formation. To examine the mechanism behind this reverse correlation, we used a combinatorial approach to determine DNA accessibility, histone occupancy, and the unique recruitment and requirement of BAF and PBAF, two functionally distinct subclasses of SWI/SNF at the LTR of HIV-infected cells before and after activation. We find that establishment and maintenance of HIV latency requires BAF, which removes a preferred nucleosome from DHS1 to position the repressive nucleosome-1 over energetically sub-optimal sequences. Depletion of BAF resulted in de-repression of HIV latency concomitant with a dramatic alteration in the LTR nucleosome profile as determined by high resolution MNase nucleosomal mapping. Upon activation, BAF was lost from the HIV promoter, while PBAF was selectively recruited by acetylated Tat to facilitate LTR transcription. Thus BAF and PBAF, recruited during different stages of the HIV life cycle, display opposing function on the HIV promoter. Our data point to the ATP-dependent BRG1 component of BAF as a putative therapeutic target to deplete the latent reservoir in patients.

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Section: Resultsmentioning

confidence: 98%

Repressive LTR Nucleosome Positioning by the BAF Complex Is Required for HIV Latency

et al. 2011

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“…TgIST represents an example of a pathogen hijacking the Mi-2/NuRD complex to regulate host gene expression and dampen immunity, although there are several examples of viral proteins interacting with Mi-2/NuRD to regulate their own gene expression (Cismasiu et al, 2008; Dembowski and DeLuca, 2015; Terhune et al, 2010). In contrast, TgIST acts by recruitment of the chromatin-modifying Mi-2/NuRD complex to STAT1 transcriptional complexes, resulting in chromatin remodeling and decreased ISG expression.…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma Effector Recruits the Mi-2/NuRD Complex to Repress STAT1 Transcription and Block IFN-γ-Dependent Gene Expression

Olias

Etheridge

Zhang

et al. 2016

Cell Host & Microbe

160

223

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Summary Interferon gamma (IFN-γ) is an essential mediator of host defense against intracellular pathogens, including the protozoan parasite Toxoplasma gondii. However, prior T. gondii infection blocks IFN-γ-dependent gene transcription, despite the downstream transcriptional activator STAT1 being activated and bound to cognate nuclear promoters. We identify the parasite effector that blocks STAT1-dependent transcription and show it is associated with recruitment of the Mi-2 Nucleosome Remodeling and Deacetylase (NuRD) complex, a chromatin-modifying repressor. This secreted effector, Toxoplasma Inhibitor of STAT1-dependent Transcription (TgIST), translocates to the host cell nucleus where it recruits Mi-2/NuRD to STAT1-dependent promoters, resulting in altered chromatin and blocked transcription. TgIST is conserved across strains, underlying their shared ability to block IFN-γ-dependent transcription. TgIST deletion results in increased parasite clearance in IFN-γ-activated cells and reduced mouse virulence, which is restored in IFN-γ-receptor deficient mice. These findings demonstrate the importance of both IFN-γ responses and the ability of pathogens to counteract these defenses.

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“…In addition, this BCL11B N-terminal domain is essential for the transcriptional repression of HIV-1 long terminal repeat (LTR) sequences which thus affects both HIV-1 replication and virus production in CD4 ϩ T lymphocytes (66). In future studies, it would be interesting to explore whether this switch between transcriptional repression and activation by phosphorylation in their MS RRKQ motifs could be generalized to other NuRD-interacting proteins, in particular to BCL11A or FOG1, two important regulators of differentiation programs during normal hematopoiesis.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4⁺ T-Cell Activation

Dubuissez

Loison

Paget

et al. 2016

Molecular and Cellular Biology

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Posttranslational modifications (PTMs) of transcription regulatory proteins allow the integration of various signaling and environmental cues into highly dynamic and controlled responses, thereby achieving coordinated gene expression programs essential for cell proliferation or differentiation.The transcription factor BCL11B/CTIP2 was independently isolated as an interacting partner of chicken ovalbumin upstream promoter transcription factor (COUP-TF) in neurons and as a tumor suppressor gene in mouse models of gamma ray-induced thymic lymphomas (1-3). Besides its expression in the central nervous system (CNS), BCL11B was shown to be widely expressed in all T-cell subsets, starting from the double-negative stage 2 (DN2 stage) and to be involved in various aspects of development, function, and survival of T cells (4). Indeed, BCL11B is a focal point essential for several checkpoints involved in T-cell commitment in early progenitors, selection at the DN2 stage, and differentiation of peripheral T cells (5-9). Furthermore, monoallelic BCL11B deletions or missense mutations have been identified in the major molecular subtypes of T-cell acute lymphoblastic leukemia (10). Therefore, these observations together with the occurrence of deletions and mutations in gamma ray-induced thymomas in mice identify BCL11B as a haploinsufficient tumor suppressor gene (11).BCL11B is essential for T-cell development and is considered a "guardian of T cell fate" (12). Its closely related paralog BCL11A is essential for normal lymphopoiesis and hemoglobin switching during erythroid differentiation (13-15). Thus, these two transcription factors appear to be key regulators of fundamental differentiation programs during normal hematopoiesis.BCL11B represses transcription of its target genes through interaction with several chromatin remodelling complexes and notably recruits NuRD complexes (nuclear remodeling and deacetylation complexes) via interaction with MTA1 and MTA2 (4,11,[16][17][18]. Although originally characterized as a sequence-specific transcriptional repressor, BCL11B also behaves as a context-dependent transcriptional activator of the IL-2 and Cot kinase genes in CD4 ϩ T-cell activation (19, 20). This dual behavior of BCL11B as a transcriptional repressor and activator is not fully understood but clearly relies on a dynamic cross talk between BCL11B PTMs. Indeed, mass spectrometry analyses of thymocytes isolated from 4-to 8-week-old mice and stimulated with a mixture of phorbol ester and calcium ionophore used as an in vitro model mimicking T-cell receptor (TCR) activation identified several mitogen-activated protein kinase (MAPK) phosphorylation sites of BCL11B and confirmed its

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BCL11B is a general transcriptional repressor of the HIV-1 long terminal repeat in T lymphocytes through recruitment of the NuRD complex

Cited by 46 publications

References 59 publications

Repressive LTR Nucleosome Positioning by the BAF Complex Is Required for HIV Latency

Repressive LTR Nucleosome Positioning by the BAF Complex Is Required for HIV Latency

Toxoplasma Effector Recruits the Mi-2/NuRD Complex to Repress STAT1 Transcription and Block IFN-γ-Dependent Gene Expression

Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4⁺ T-Cell Activation

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BCL11B is a general transcriptional repressor of the HIV-1 long terminal repeat in T lymphocytes through recruitment of the NuRD complex

Cited by 46 publications

References 59 publications

Repressive LTR Nucleosome Positioning by the BAF Complex Is Required for HIV Latency

Repressive LTR Nucleosome Positioning by the BAF Complex Is Required for HIV Latency

Toxoplasma Effector Recruits the Mi-2/NuRD Complex to Repress STAT1 Transcription and Block IFN-γ-Dependent Gene Expression

Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4+ T-Cell Activation

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Protein Kinase C-Mediated Phosphorylation of BCL11B at Serine 2 Negatively Regulates Its Interaction with NuRD Complexes during CD4⁺ T-Cell Activation