Reproductive Cycle Regulation of Nuclear Import, Euchromatic Localization, and Association with Components of Pol II Mediator of a Mammalian Double-Bromodomain Protein

Crowley, Thomas E.; Kaine, Emily M.; Yoshida, Manabu; Nandi, Anindita; Wolgemuth, Debra J.

doi:10.1210/me.2001-0353

Cited by 44 publications

(43 citation statements)

References 34 publications

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“…Similarly, cytoplasmic localization of Brd2 has been previously described in differentiating neurons of the mouse embryo . In addition, Brd2 delocalization was originally reported in mouse 3T3 cells following serum deprivation and has been also described in the mouse mammary epithelia during pregnancy (Crowley et al, 2002). Regardless of whether cytoplasmic localization of Brd2 is a consequence of Ptn interaction, what appears relevant to our hypothesis is that Ptn antagonizes Brd2 nuclear function, that is, the Brd2 cell-cyclestimulating activity, which opposes to neuronal differentiation.…”

Section: Discussionmentioning

confidence: 52%

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: 52%

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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“…This family includes several somatic members, and some have been functionally characterized (12). One of these somatic members is human Ring3, which interacts with several transcription factors, including E2F, depending on the presence of acetylated histone H3 and H4 tails (7). The mouse homologue of Ring3, Fsrg1, was found to be associated with euchromatin, reinforcing the idea of the association of this protein with the control of transcription (7).…”

Section: Discussionmentioning

confidence: 79%

“…One of these somatic members is human Ring3, which interacts with several transcription factors, including E2F, depending on the presence of acetylated histone H3 and H4 tails (7). The mouse homologue of Ring3, Fsrg1, was found to be associated with euchromatin, reinforcing the idea of the association of this protein with the control of transcription (7). Moreover, another member of this family, Brd4 was found to interact with replication factor C and to inhibit DNA replication in vivo, after overexpression, as well as in vitro (29).…”

Section: Discussionmentioning

confidence: 99%

Acetylation-Dependent Chromatin Reorganization by BRDT, a Testis-Specific Bromodomain-Containing Protein

Pivôt-Pajot

Caron

Govin

et al. 2003

Molecular and Cellular Biology

258

205

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The association between histone acetylation and replacement observed during spermatogenesis prompted us to consider the testis as a source for potential factors capable of remodelling acetylated chromatin. A systematic search of data banks for open reading frames encoding testis-specific bromodomain-containing proteins focused our attention on BRDT, a testis-specific protein of unknown function containing two bromodomains. BRDT specifically binds hyperacetylated histone H4 tail depending on the integrity of both bromodomains. Moreover, in somatic cells, the ectopic expression of BRDT triggered a dramatic reorganization of the chromatin only after induction of histone hyperacetylation by trichostatin A (TSA). We then defined critical domains of BRDT involved in its activity. Both bromodomains of BRDT, as well as flanking regions, were found indispensable for its histone acetylation-dependent remodelling activity. Interestingly, we also observed that recombinant BRDT was capable of inducing reorganization of the chromatin of isolated nuclei in vitro only when the nuclei were from TSA-treated cells. This assay also allowed us to show that the action of BRDT was ATP independent, suggesting a structural role for the protein in the remodelling of acetylated chromatin. This is the first demonstration of a large-scale reorganization of acetylated chromatin induced by a specific factor.The histone code hypothesis postulating a role for posttranslational modifications of histones in the control of chromatin structure and function (39, 41) is now supported by a large body of data. The milestone of this hypothesis is the existence of protein domains capable of specifically recognizing particular posttranslational histone modifications (22). To date, at least two distinct domains have been shown to interact with modified histones: bromodomains, recognizing acetylated lysines (43), and some chromodomains, interacting with methylated lysine 9 present in the histone H3 N-terminal tail (2,19,20,25,40).Bromodomains are conserved modules present in many chromatin-and transcription-related proteins, including histone acetyltransferases and chromatin remodelling factors (11). The first bromodomain shown to specifically interact with an acetylated peptide, corresponding to the histone H4 N terminus, was that of P/CAF (9). Further investigations showed that bromodomains can also recognize acetylated lysines in nonhistone proteins and play an essential role in establishing new acetylation-dependent functions (10, 33, 37). Bromodomain-containing proteins are therefore likely to interpret signals generated by protein acetylation and, more specifically in the case of chromatin, mediate functions depending on histone acetylation (1,16,26,31).Interestingly, there is at least one physiological situation where histone acetylation can unambiguously be linked to chromatin remodelling. In many species, including the fly, trout, rooster, rat, mouse, and human, male germ cell nuclear maturation is characterized by the hyperacetylation of histones ...

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“…Brd2 and Brd3 allow transcription by RNA polymerase II (RNA pol II) through hyperacetylated chromosomes using in vitro systems (29). Brd2 associates with various transcription regulatory proteins, including E2F transcription factors, histone deacetylases, and the RNA polymerase II Mediator complex (9,10,25,44). Brd4 regulates gene expression and is unique among the human BET family proteins in having a carboxyl-terminal domain (CTD) not present in the other BET family proteins.…”

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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

475

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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Reproductive Cycle Regulation of Nuclear Import, Euchromatic Localization, and Association with Components of Pol II Mediator of a Mammalian Double-Bromodomain Protein

Cited by 44 publications

References 34 publications

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

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

Acetylation-Dependent Chromatin Reorganization by BRDT, a Testis-Specific Bromodomain-Containing Protein

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

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