The association of brd2 with juvenile

See other articles in PMC that cite the published article. Abstract The acetylation of histone lysine is central to providing the dynamic regulation of chromatin-based gene transcription.

The association of brd2 with juvenile

Wolgemuth Find articles by Debra J. Brd2 is expressed in proliferating neuronal progenitors, displays cell-cycle-stimulating activity and, when overexpressed, impairs neuronal differentiation.

Epilepsia and paroxyzmal conditions

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 Ptn-mediated antagonism of Brd2 in a cell differentiation model and in two embryonic processes associated with the neural tube: Finally, we investigated the mechanisms of Ptn-mediated antagonism and determined that Ptn destabilizes the association of Brd2 with chromatin.

Thus, Ptn-mediated Brd2 antagonism emerges as a modulation system accounting for the balance between cell proliferation and differentiation in the vertebrate nervous system. Accurate control of these processes is a challenge for regenerative medicine when applying cell therapies.

Members of the bromodomain and extra terminal BET family of transcriptional co-regulators have essential roles in cell cycle progression Belkina et al. Interestingly, some BET members have been additionally associated with cell differentiation.

In this regard, the family member bromodomain-containing protein 2 Brd2besides interacting with the transcription factor E2F and controlling expression of cyclin A2 and D1 in proliferating cells Belkina et al. Four BET proteins have been described in vertebrates, Brd2, Brd3, Brd4 and Brdt, which are broadly expressed with the exception of Brdt, where expression is restricted to the male germ line Crowley et al.

BET proteins, by means of two N-terminal bromodomains, recognize and associate with acetylated histones on chromatin Kanno et al. In contrast to most proteins, including other bromodomain-containing proteins, some of the BET family members have the ability to remain attached to the chromosomes during mitosis Dey et al.

The association of brd2 with juvenile

Although binding of BET proteins to the chromatin depends on the integrity of the bromodomains Kanno et al. Knockout mice of BET family members have highlighted the relevance of these proteins for development and survival. Thus, Brd4 and Brd2 mutant mice die at early post-implantation and E Mouse embryonic fibroblasts derived from Brd4 and Brd2 mutant embryos display proliferative defects, which, to a lesser extent, are also observed in heterozygous cells Houzelstein et al.

In addition, knockdown of Brd4 in cultured cells leads to cell cycle arrest Mochizuki et al. Interestingly, reduced expression of Brd2 in mice produces a distinct hypomorphic phenotype with extreme obesity and hyperinsulinemia, but enhanced glucose tolerance and low blood glucose Wang et al.

In the developing neural tube, proliferation occurs in the ventricular zone, close to the lumen, and neuronal differentiation requires proliferating progenitors to exit the cell cycle and, subsequently, migrate to the pial surface, or mantle layer, to accomplish differentiation.

Besides being expressed in neural progenitors, Brd2 is also detected in differentiating neurons of the mantle layer in the developing spinal cord Crowley et al. It has been reported that Brd2 stimulates cell cycle progression Sinha et al. Thus, the prominent role Brd2 displays during cell proliferation raises the question about its presence in differentiating neurons.

To reconcile these observations and to better understand Brd2 function we have looked for Brd2-interacting proteins. From a previous two-hybrid screening Garcia-Gutierrez et al.

Ptn is abundantly expressed in the developing nervous system, and together with its homologue midkine Mdkcomprise a family of secreted heparin-binding growth factors Kadomatsu and Muramatsu, Its neuroprotective properties, together with its capacity to promote neurite outgrowth, are important for nerve regeneration Jin et al.

In this work, we describe Ptn—Brd2 interaction during neuronal differentiation. Our results indicate that Ptn enhances induced neuronal differentiation by antagonizing Brd2 cell-cycle-stimulating activity.

Thus, we propose that Ptn-mediated antagonism accounts for the occurrence of neuronal differentiation in the presence of Brd2. RESULTS Ptn interacts with Brd2 To obtain insight into the function of Brd2 and in particular, to begin to explain how the role of Brd2 in regulating the cell cycle can be understood in light of its presence in differentiating neurons, we previously had performed a yeast two-hybrid screening with an day-old mouse embryo cDNA library Garcia-Gutierrez et al.

At this stage, development of the neural tube is advanced and contains both neural progenitors and differentiating neurons. Among the Brd2 partners we identified was Ptn, previously shown to be expressed following retinoic acid RA -mediated induction of neuronal differentiation in mouse teratocarcinoma P19 cells Brunet-de Carvalho et al.The present association study tested whether genetic variation of BRD2 confers also susceptibility to PPR.

All study participants were of German descent, comprising subjects exhibiting PPR (types I–IV) and healthy controls.

References

Overexpression of Brd2 protein with oncogenic ras transactivates E2F-dependent promoters of the cell cycle regulatory genes dihydrofolate reductase, cyclin D1, cyclin A and cyclin E. highly significant linkage disequilibrium between juvenile myoclonic epilepsy and a core haplotype of five single-nucleotide-polymorphism and microsatellite.

Juvenile myoclonic epilepsy (JME) is a common form of generalized epilepsy that starts in adolescence. A major JME susceptibility locus (EJM1) was mapped to chromosomal region 6p21 in three independent linkage studies, and association was reported between JME and a .

b SNP-associated variants of BRD2. However. a Human Genome Nomenclature Committee gene symbol in bold letters. pyknoleptic childhood absence epilepsy.

Epilepsy Juvenile Myoclonic Publications | PubFacts

linkage disequili‐ brium is strongest and covers the widest region of a chromosome when the epilepsy allele is of recent origin). Brd2 haplo-insufficiency has been linked to neuronal deficits and epilepsy.

L. Velisek et al., “GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy,” PLoS One 6(8): e () SNPs in various bromodomain-containing proteins have also been linked to.

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The association of brd2 with juvenile
Juvenile myoclonic epilepsy - Wikipedia