The C-terminal domain of Brd2 is important for chromatin interaction and regulation of transcription and alternative splicing

Hnilicová, Jarmila; Hozeifi, Samira; Stejskalová, Eva; Dušková, Eva; Poser, Ina; Humpolíčková, Jana; Hof, Martin; Staněk, David

doi:10.1091/mbc.e13-06-0303

Cited by 50 publications

(53 citation statements)

References 79 publications

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“…First, we asked whether Brd2 in cultured progenitors was also the most prominent BET protein to be detected in the oligodendrocyte lineage cells (Figure 6A), which was consistent with our in vivo studies in developing myelinating tracts (Figure 2A). We then expressed either a wild type eGFP-tagged Brd2 (eGFP-Brd2 wt ) molecule or a mutant form of Brd2 (eGFP-Brd2 mut ) lacking the acetyl-lysine binding domains in the first and second BrD of the protein molecule (Hnilicová J et al, 2013) in Oli neu cells and asked whether the two molecules were differentially distributed within the nucleus of transfected cells. While the eGFP-Brd2 wt transfected cells were characterized by a nuclear diffuse distribution, those transfected with the mutant eGFP-Brd2 mut - lacking the ability to bind acetyl-lysine - showed a very distinctive punctate distribution (Figure 6B).…”

Section: Resultsmentioning

confidence: 99%

Selective Chemical Modulation of Gene Transcription Favors Oligodendrocyte Lineage Progression

Gacias

Gerona‐Navarro

Plotnikov

et al. 2014

Chemistry & Biology

134

168

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SUMMARY Lysine acetylation regulates gene expression through modulating protein-protein interactions in chromatin. Chemical inhibition of acetyl-lysine binding bromodomains of the major chromatin regulators BET (bromodomain and extra-terminal domain) proteins, has been shown to effectively block cell proliferation in cancer and inflammation. However, whether selective inhibition of individual BET bromodomains has distinctive functional consequences, remains only partially understood. In this study, we show that selective chemical inhibition of the first bromodomain of BET proteins using our newly designed small molecule inhibitor, Olinone, accelerated the progression of mouse primary oligodendrocyte progenitors towards differentiation, while inhibition of both bromodomains of BET proteins hindered differentiation. This effect was target-specific, as it was not detected in cells treated with inactive analogues and independent of any effect on proliferation. Therefore, selective chemical modulation of individual bromodomains, rather than use of broad-based inhibitors may enhance regenerative strategies in disorders characterized by myelin loss such as aging and neurodegeneration.

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Section: Resultsmentioning

confidence: 99%

Selective Chemical Modulation of Gene Transcription Favors Oligodendrocyte Lineage Progression

Gacias

Gerona‐Navarro

Plotnikov

et al. 2014

Chemistry & Biology

134

168

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“…The explanation is that, although histone acetylation is enriched near the TSS of active genes, TSS are nucleosome free and there are no histone acetyl marks for BET proteins to bind. Although it is reasonably clear that the Brd2, Brd3, and Brd4 proteins bind to acetylated residues on histone tails, exactly which modified histone residues are most tightly bound by these three Brd proteins, and the degree to which the binding sites of the various Brd proteins are influenced by other interactions, is not well understood (15).…”

Section: Discussionmentioning

confidence: 99%

“…Several groups identified bromodomain and extraterminal (BET) proteins (BRD2, BRD3, and BRD4) as the major host factors that specifically interact with MLV IN and mediate the preferential integration of MLV near TSS (9)(10)(11)(12). BET proteins bind to acetylated histone tails via their bromodomains (13)(14)(15). The ET domains of BET proteins selectively bind to the C-terminal domain (CTD) of MLV IN.…”

Section: Importancementioning

confidence: 99%

Enhancers Are Major Targets for Murine Leukemia Virus Vector Integration

Ravin

Theobald

et al. 2014

J Virol

131

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Retroviral vectors have been used in successful gene therapies. However, in some patients, insertional mutagenesis led to leukemia or myelodysplasia. Both the strong promoter/enhancer elements in the long terminal repeats (LTRs) of murine leukemia virus (MLV)-based vectors and the vector-specific integration site preferences played an important role in these adverse clinical events. MLV integration is known to prefer regions in or near transcription start sites (TSS). Recently, BET family proteins were shown to be the major cellular proteins responsible for targeting MLV integration. Although MLV integration sites are significantly enriched at TSS, only a small fraction of the MLV integration sites (<15%) occur in this region. To resolve this apparent discrepancy, we created a high-resolution genome-wide integration map of more than one million integration sites from CD34 ؉ hematopoietic stem cells transduced with a clinically relevant MLV-based vector. The integration sites form ϳ60,000 tight clusters. These clusters comprise ϳ1.9% of the genome. The vast majority (87%) of the integration sites are located within histone H3K4me1 islands, a hallmark of enhancers. The majority of these clusters also have H3K27ac histone modifications, which mark active enhancers. The enhancers of some oncogenes, including LMO2, are highly preferred targets for integration without in vivo selection. IMPORTANCEWe show that active enhancer regions are the major targets for MLV integration; this means that MLV preferentially integrates in regions that are favorable for viral gene expression in a variety of cell types. The results provide insights for MLV integration target site selection and also explain the high risk of insertional mutagenesis that is associated with gene therapy trials using MLV vectors.

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“…We focused on H4 acetylation, because we previously observed the highest changes in H4 acetylation after HDAC inhibition at the FN1 gene. 52 We normalized the H4 acetylation signal to the total H3 signal to rule out whether the increased H4 acetylation signal was being caused by an increase in nucleosome occupancy. We observed reduced H4 acetylation at promoters with deleted CRE sites (Fig.…”

Section: P300 Knockdown Changes Alternative Splicingmentioning

confidence: 99%

“…[49][50][51] Recently, we showed the acetylated histone binding protein Brd2, which regulates the alternative splicing of several hundred genes, is also preferentially found at promoters of target genes. 52 However, histone acetylation modulates alternative splicing of several hundred genes. here, we tested the role of the histone acetyltransferase p300 in alternative splicing and showed that knockdown of p300 promotes inclusion of the fibronectin (FN1) alternative eDB exon.…”

Section: Introductionmentioning

confidence: 99%

CRE promoter sites modulate alternative splicing via p300-mediated histone acetylation

2014

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The C-terminal domain of Brd2 is important for chromatin interaction and regulation of transcription and alternative splicing

Cited by 50 publications

References 79 publications

Selective Chemical Modulation of Gene Transcription Favors Oligodendrocyte Lineage Progression

Selective Chemical Modulation of Gene Transcription Favors Oligodendrocyte Lineage Progression

Enhancers Are Major Targets for Murine Leukemia Virus Vector Integration

CRE promoter sites modulate alternative splicing via p300-mediated histone acetylation

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