A prospective study was conducted in the Neonatal Intensive Care Unit of the University Children's hospital between September 1, 2008 and November 30, 2010. The entry criteria were (1) preterm birth below 32 weeks gestational age, (2) birthweight<1500g (VLBW). During the follow-up period, bronchopulmonary dysplasia (BPD) was diagnosed in 68 (61%) infants, including 40 (36%) children with mild disease, 13 (12%) with moderate and 15 (13%) with severe BPD. Forty-three babies served as a control group (no BPD).
Gene expression profiling in preterm infants: new aspects of bronchopulmonary dysplasia development.
Sex, Specimen partView Samples
Perinatal asphyxia is detrimental to the newborn baby and the use of supplemental oxygen during resuscitation may worsen the prognosis of these babies. The mechanism behind hyperoxic injury is not fully understood and our aim was to investigate four oxygen therapies following hypoxia and these effects on transcriptional activity.
Transcriptome profiling of the newborn mouse brain after hypoxia-reoxygenation: hyperoxic reoxygenation induces inflammatory and energy failure responsive genes.
Specimen partView Samples
Altered patterns of transcription factor (TF) binding are now accepted as a hallmark of many aggressive cancers including prostate and breast cancers1,2. This implies that underlying global changes in chromatin accessibility may drive cancer progression, as previously hypothesized3-5. In addition there are epigenetic readers such as bromodomain containing protein 4 (BRD4), which have been shown to associate with these TFs6-8 and also to contribute to aggressive cancers of many types8,9 including prostate cancer (PC)6,10. Here we show for the first time that formaldehyde-assisted isolation of regulatory elements followed by sequencing (FAIRE-seq) applied to human prostate tumors tissue can define castrate-resistant prostate cancer (CRPC) and can be used to inform the discovery of gene-level classifiers for therapy. In addition, we show that the androgen receptor (AR) overexpression alone is a primary driver for chromatin relaxation and that this effect can be reversed using bromodomain inhibitors. We also report that bromodomain-containing proteins (BRDs) are overexpressed in advanced CRPCs and that ATAD2 and BRD2 have prognostic value. In conclusion, this is the first study demonstrating a major impact of BRDs on chromatin accessibility in CRPC in patient samples. Consequently, targeting bromodomains provides a compelling rational for combination therapy in which BRD-mediated TF binding is enhanced or modified as cancer progresses.
Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer.
Prostate cancer is the most common non-cutaneous cancer in men. The androgen receptor (AR) a ligand-activated transcription factor, constitutes the main drug target for advanced cases of the disease. However, a variety of other transcription factors and signalling networks have been shown to be altered in patients and to influence AR activity. The oncogenic transcription factor c-Myc has been studied extensively in multiple malignancies, but its impact on AR activity in prostate cancer remains elusive. In this study we assessed the impact of clinically relevant levels of c-Myc overexpression on AR activity and transcriptional output. We found that c-Myc and the AR share a substantial amount of binding sites, which exhibit enhancer-like characteristics. Interestingly, c-Myc overexpression altered global AR chromatin occupancy and antagonised a subset of androgen-induced genes. Furthermore, c-Myc overexpression modified histone marks, most notably H3K4me1 and H3K27me3. Lastly, we validated the antagonistic relationship between c-Myc and two AR target genes, KLK3 and GNMT, in patient samples.
c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks.
-myosin heavy chain promoter controlled MerCreMer expression enables conditional, cardiomyocyte specific and tamoxifen dependent gene inactivation of floxed genes. Administration of tamoxifen has been linked to development of acute and transient cardiomyopathy. The mechanism for this is unknown.
Cre-loxP DNA recombination is possible with only minimal unspecific transcriptional changes and without cardiomyopathy in Tg(alphaMHC-MerCreMer) mice.
Sex, Specimen part, TimeView Samples
The aim of the present study was to examine potential differences in the regulation of myocardial ECM constituents, in mice that develop hypertrophy only (ABnonHF) and in mice that develop overt heart failure (ABHF) as response to pressure overload.
Differential regulation of extracellular matrix constituents in myocardial remodeling with and without heart failure following pressure overload.
Specimen part, TreatmentView Samples
Epigenetic environment of histone H3.3 on promoters revealed by integration of imaging and genome-scale chromatin and methyl-DNA immunoprecipitation information.
Chromatin environment of histone variant H3.3 revealed by quantitative imaging and genome-scale chromatin and DNA immunoprecipitation.
Specimen partView Samples