Search

BRDT, a member of the BET family of double bromodomain-containing proteins, is essential for spermatogenesis in the mouse and has been postulated to be a key regulator of transcription in meiotic and post-meiotic cells. To understand the function of BRDT in these processes, we first characterized the genome-wide distribution of the BRDT binding sites, in particular within gene units, by ChIP-Seq analysis of enriched fractions of pachytene spermatocytes and round spermatids. In both cell types, BRDT binding sites were mainly located in promoters, first exons, and introns of genes. BRDT binding sites in promoters overlapped with several histone modifications and histone variants associated with active transcription, and were enriched for consensus sequences for specific transcription factors, including MYB, RFX, ETS, and ELF1 in pachytene spermatocytes, and JunD, c-Jun, CRE, and RFX in round spermatids. Subsequent integration of the ChIP-seq data with available transcriptome data revealed that stage-specific gene expression programs are associated with BRDT binding to their gene promoters, with most of the BDRT-bound genes being upregulated. Gene Ontology analysis further identified unique sets of genes enriched in diverse biological processes essential for meiosis and spermiogenesis between the two cell types, suggesting distinct developmentally stage-specific functions for BRDT. Taken together, our data suggest that BRDT cooperates with different transcription factors at distinctive chromatin regions within gene units to regulate diverse downstream target genes that function in male meiosis and spermiogenesis.

We retrospectively investigated the prognostic impact of molecular phenotypes in patients with recurrent anaplastic glioma treated with prolonged administration of temozolomide (TMZ). Malignant gliomas have a dismal prognosis despite the available multimodal treatments. We reviewed 87 patients who were diagnosed with recurrent anaplastic gliomas between March 2004 and June 2010, and 58 were enrolled for analysis. In the cohort, 21 patients had anaplastic oligodendrogliomas, 18 anaplastic oligoastrocytomas and 19 anaplastic astrocytomas. All patients were initially treated with surgical resection or biopsy followed by involved-field radiotherapy. At recurrence, patients were treated with 150–200 mg/m 2 of TMZ on days 1–5 in 28 day cycles until disease progression. We evaluated the association of molecular phenotypes, including 1p19q deletion, O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, isocitrate dehydrogenase-1 (IDH1) mutation and other clinico-histopathological findings with treatment outcome. During the mean follow-up period of 34.6 months, 33 patients were still alive (56.9%). Median survival from recurrence was 39.7 months (95% confidence interval [CI] 22.7–56.7). Time to progression from administration of TMZ was 6.4 months (95% CI 5.0–7.8). Univariate analysis demonstrated that the presence of the IDH1 mutation was closely associated with treatment response (8.4 versus 3.8 months; p = 0.015). Oligodendroglial lineage, 1p19q deletion status and MGMT promoter methylation status were not independent variables for determining the TMZ treatment outcome. In recurrent anaplastic gliomas, TMZ treatment is an effective modality regardless of MGMT methylation status or histological type. The IDH1 mutation has the most powerful prognostic impact on overall patient survival.

The human telomeric protein TRF2 is required to protect chromosome ends by facilitating their organization into the protective capping structure. Post-translational modifications of TRF2 such as phosphorylation, ubiquitination, SUMOylation, methylation and poly(ADP-ribosyl)ation have been shown to play important roles in telomere function. Here we show that TRF2 specifically interacts with the histone acetyltransferase p300, and that p300 acetylates the lysine residue at position 293 of TRF2. We also report that p300-mediated acetylation stabilizes the TRF2 protein by inhibiting its ubiquitin-dependent proteolysis and is required for efficient telomere binding of TRF2. Furthermore, overexpression of the acetylation-deficient mutant, K293R, induces DNA-damage response foci at telomeres, thereby leading to induction of impaired cell growth, cellular senescence and altered cell cycle distribution. A small but significant number of metaphase chromosomes show no telomeric signals at chromatid ends, suggesting an aberrant telomere structure. These findings demonstrate that acetylation of TRF2 by p300 plays a crucial role in the maintenance of functional telomeres as well as in the regulation of the telomere-associated DNA-damage response, thus providing a new route for modulating telomere protection function.

Background and Objective Surgical treatment for pineal tumors is technically challenging—weighing the risks and benefits of microsurgical resection for the patient with a pineal tumor versus settling for an endoscopic third ventriculostomy and biopsy is sometimes difficult. Traditional microsurgical resection for pineal region tumors has typically required large open craniotomies and involvement or retraction of neural tissue with significant mortality and morbidity. With the advancement of high-resolution fiber optics, a fully endoscopic, supracerebellar, infratentorial approach, without any cerebellar retraction or manipulation of neural tissue, is introduced for the gross total resection of pineal region tumors. Conclusion As an endoscopic modification of the open craniotomy procedure, this technique combines the advantages and benefits of both open microsurgical resection and minimally invasive endoscopic surgeries.

The telomeric protein TRF1 negatively regulates telomere length by inhibiting telomerase access at the telomere termini, suggesting that the protein level of TRF1 at telomeres is tightly regulated. Regulation of TRF1 protein abundance is essential for proper telomere function and occurs primarily through post-translational modifications of TRF1. Here we describe RLIM, a RING H2 zinc finger protein with intrinsic ubiquitin ligase activity, as a TRF1-interacting protein. RLIM increases TRF1 turnover by targeting it for degradation by the proteasome in a ubiquitin-dependent manner, independently of Fbx4, which is known to interact with and negatively regulate TRF1. Whereas overexpression of RLIM decreases the level of TRF1 protein, depletion of endogenous RLIM expression by small hairpin RNA increases the level of TRF1 and leads to telomere shortening, thereby impairing cell growth. These results demonstrate that RLIM is involved in the negative regulation of TRF1 function through physical interaction and ubiquitin-mediated proteolysis. Hence, RLIM represents a new pathway for telomere maintenance by modulating the level of TRF1 at telomeres.