The chromatin-targeting protein Brd2 is required for neural tube closure and embryogenesis

Gyuris, Aron; Donovan, Diana; Seymour, Kimberly A.; Lovasco, Lindsay A.; Smilowitz, Nathaniel R.; Halperin, Anthony L.P.; Kłysik, Jan; Freiman, Richard N.

doi:10.1016/j.bbagrm.2009.03.005

Cited by 92 publications

(83 citation statements)

References 44 publications

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“…Our results do not exclude specific roles of Brd2 during the neuronal differentiation program because, as mentioned above, Brd2 protein, besides being detected in neural progenitors in the developing neural tube, also appears in differentiating neurons along the dorsoventral axis, including interneurons, motoneurons and sensory neurons . Although several reports have suggested an involvement of Brd2 in the process of neuronal differentiation (Gyuris et al, 2009;Tsume et al, 2012;Velíšek et al, 2011), specific conditional knockout mice are required to accurately assess this issue. Finally, despite functional redundancy between Ptn and Mdk, an interesting developmental phenotype associated with the single Ptn mutation in mice supports our model: absence of Ptn results in prolonged proliferation and therefore in impaired neurogenesis in the cerebral cortex (Hienola et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, some BET members have been additionally associated with cell differentiation. In this regard, the family member bromodomain-containing protein 2 (Brd2), besides interacting with the transcription factor E2F and controlling expression of cyclin A2 and D1 in proliferating cells (Belkina et al, 2014;Denis et al, 2000;Garcia-Gutierrez et al, 2012;LeRoy et al, 2008;Sinha et al, 2005), is expressed in differentiating neurons , which might be linked to the neural tube closure defects observed in Brd2-knockout mouse embryos and to the association of mutations in the BRD2 locus with human juvenile myoclonic epilepsy (Gyuris et al, 2009;Shang et al, 2009;Velíšek et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

García-Gutiérrez¹,

Juárez-Vicente²,

Wolgemuth³

et al. 2014

Journal of Cell Science

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Bromodomain-containing protein 2 (Brd2) is a BET family chromatin adaptor required for expression of cell-cycle-associated genes and therefore involved in cell cycle progression. Brd2 is expressed in proliferating neuronal progenitors, displays cell-cycle-stimulating activity and, when overexpressed, impairs neuronal differentiation. Paradoxically, Brd2 is also detected in differentiating neurons. To shed light on the role of Brd2 in the transition from cell proliferation to differentiation, we had previously looked for proteins that interacted with Brd2 upon induction of neuronal differentiation. Surprisingly, we identified the growth factor pleiotrophin (Ptn). Here, we show that Ptn antagonized the cell-cycle-stimulating activity associated with Brd2, thus enhancing induced neuronal differentiation. Moreover, Ptn knockdown reduced neuronal differentiation. We analyzed Ptnmediated antagonism of Brd2 in a cell differentiation model and in two embryonic processes associated with the neural tube: spinal cord neurogenesis and neural crest migration. Finally, we investigated the mechanisms of Ptn-mediated antagonism and determined that Ptn destabilizes the association of Brd2 with chromatin. Thus, Ptnmediated Brd2 antagonism emerges as a modulation system accounting for the balance between cell proliferation and differentiation in the vertebrate nervous system.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

García-Gutiérrez¹,

Juárez-Vicente²,

Wolgemuth³

et al. 2014

Journal of Cell Science

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“…Mutations of fs(1)h cause segmental abnormalities, including missing organs and homeotic transformations in the progeny of mutant females in Drosophila (13). Knockout of Brd4 or Brd2 in mice results in early embryonic lethality (18,21).The BET proteins have been shown to be important players in human disease, including viral infections and cancer. Several different viruses target the individual BET proteins for a variety of purposes but often to regulate viral and cellular transcription (4,7,31,37,41,45,57,60).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

The Brd4 Extraterminal Domain Confers Transcription Activation Independent of pTEFb by Recruiting Multiple Proteins, Including NSD3

Rahman

Sowa

Ottinger

et al. 2011

Molecular and Cellular Biology

473

490

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Bromodomain protein 4 (Brd4) plays critical roles in development, cancer progression, and virus-host pathogenesis. To gain mechanistic insight into the various biological functions of Brd4, we performed a proteomic analysis to identify and characterize Brd4-associated cellular proteins. We found that the extraterminal (ET) domain, whose function has to date not been determined, interacts with NSD3, JMJD6, CHD4, GLTSCR1, and ATAD5. These ET-domain interactions were also conserved for Brd2 and Brd3, the other human BET proteins tested. We demonstrated that GLTSCR1, NSD3, and JMJD6 impart a pTEFb-independent transcriptional activation function on Brd4. NSD3 as well as JMJD6 is recruited to regulated genes in a Brd4-dependent manner. Moreover, we found that depletion of Brd4 or NSD3 reduces H3K36 methylation, demonstrating that the Brd4/NSD3 complex regulates this specific histone modification. Our results indicate that the Brd4 ET domain through the recruitment of the specific effectors regulates transcriptional activity. In particular, we show that one of these effectors, NSD3, regulates transcription by modifying the chromatin microenvironment at Brd4 target genes. Our study thus identifies the ET domain as a second important transcriptional regulatory domain for Brd4 in addition to the carboxyl-terminal domain (CTD) that interacts with pTEFb.One mechanism underlying the regulation of gene expression is the targeting of multiprotein complexes to modified histones, which then alters the chromatin microenvironment to stimulate or inhibit gene expression. The bromodomains and extraterminal (BET) domain family of proteins are characterized by the presence of two conserved domains, the tandem, amino-terminal bromodomains (BDI and BDII), which bind acetylated chromatin, and an extraterminal (ET) domain, whose function is unknown. The BET family is conserved from yeast to mammals and includes Saccharomyces cerevisiae bromodomain factor 1 (bdf1) and bromodomain factor 2 (bdf2), Drosophila melanogaster female sterile homeotic [fs(1)h], and mammalian Brd2, Brd3, Brd4, and testes/oocyte-specific BrdT/ Brd6. In yeast, deletion of bdf1 leads to a reduced growth rate and deletion of both bdf1 and bdf2 is lethal (27). Mutations of fs(1)h cause segmental abnormalities, including missing organs and homeotic transformations in the progeny of mutant females in Drosophila (13). Knockout of Brd4 or Brd2 in mice results in early embryonic lethality (18,21).The BET proteins have been shown to be important players in human disease, including viral infections and cancer. Several different viruses target the individual BET proteins for a variety of purposes but often to regulate viral and cellular transcription (4,7,31,37,41,45,57,60). The papillomavirus E2 proteins bind to Brd4, and some utilize this interaction in tethering the viral genomes to mitotic chromosomes (1,3,57,59). The papillomavirus E2 transcriptional activation functions are also mediated through Brd4 (35,41,42). With regard to human cancer, the Brd4-NUT and Brd3-NUT fusio...

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“…It remains unclear how BRD2 and BRD3 can substitute for one another and whether BRD3 can functionally replace BRD2 at all genes. While knockout of BRD2 or BRD4 in mice results in early embryonic lethality (Houzelstein et al, 2002;Gyuris et al, 2009;Shang et al, 2009), a BRD3 knockout mouse has not been reported.…”

Section: Brd3 ((Bromodomain Containing 3)mentioning

confidence: 99%

BRD3 (bromodomain containing 3)

Werner¹,

Hsu²,

Blobel³

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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BRD3 is a ubiquitously expressed member of the bromodomain and extraterminal motif (BET) family of proteins that use their tandem N-terminal bromodomains to associate with acetylated histones and transcription factors. Translocations involving BRD3 and NUT generate oncogenic fusion proteins that drive NUT midline carcinoma (NMC), an aggressive squamous cell malignancy. In addition, small molecule inhibitors that target the bromodomain-acetyl lysine interaction of all BET proteins are in clinical development for both hematologic malignancies and diverse solid tumors.

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The chromatin-targeting protein Brd2 is required for neural tube closure and embryogenesis

Cited by 92 publications

References 44 publications

Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

Pleiotrophin antagonizes Bromodomain-containing protein 2 (Brd2) during neuronal differentiation

The Brd4 Extraterminal Domain Confers Transcription Activation Independent of pTEFb by Recruiting Multiple Proteins, Including NSD3

BRD3 (bromodomain containing 3)

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