Genomic analysis of expressed sequence tags in American black bear Ursus americanus

<p>Abstract</p> <p>Background</p> <p>Species of the bear family (<it>Ursidae</it>) are important organisms for research in molecular evolution, comparative physiology and conservation biology, but relatively little genetic sequence information is available for this group. Here we report the development and analyses of the first large scale Expressed Sequence Tag (EST) resource for the American black bear (<it>Ursus americanus</it>).</p> <p>Results</p> <p>Comprehensive analyses of molecular functions, alternative splicing, and tissue-specific expression of 38,757 black bear EST sequences were conducted using the dog genome as a reference. We identified 18 genes, involved in functions such as lipid catabolism, cell cycle, and vesicle-mediated transport, that are showing rapid evolution in the bear lineage Three genes, Phospholamban (<it>PLN</it>), cysteine glycine-rich protein 3 (<it>CSRP3</it>) and Troponin I type 3 (<it>TNNI3</it>), are related to heart contraction, and defects in these genes in humans lead to heart disease. Two genes, biphenyl hydrolase-like (<it>BPHL</it>) and <it>CSRP3</it>, contain positively selected sites in bear. Global analysis of evolution rates of hibernation-related genes in bear showed that they are largely conserved and slowly evolving genes, rather than novel and fast-evolving genes.</p> <p>Conclusion</p> <p>We provide a genomic resource for an important mammalian organism and our study sheds new light on the possible functions and evolution of bear genes.</p

Analysis of Gene Regulatory Networks in the Mammalian Circadian Rhythm

Circadian rhythm is fundamental in regulating a wide range of cellular, metabolic, physiological, and behavioral activities in mammals. Although a small number of key circadian genes have been identified through extensive molecular and genetic studies in the past, the existence of other key circadian genes and how they drive the genomewide circadian oscillation of gene expression in different tissues still remains unknown. Here we try to address these questions by integrating all available circadian microarray data in mammals. We identified 41 common circadian genes that showed circadian oscillation in a wide range of mouse tissues with a remarkable consistency of circadian phases across tissues. Comparisons across mouse, rat, rhesus macaque, and human showed that the circadian phases of known key circadian genes were delayed for 4–5 hours in rat compared to mouse and 8–12 hours in macaque and human compared to mouse. A systematic gene regulatory network for the mouse circadian rhythm was constructed after incorporating promoter analysis and transcription factor knockout or mutant microarray data. We observed the significant association of cis-regulatory elements: EBOX, DBOX, RRE, and HSE with the different phases of circadian oscillating genes. The analysis of the network structure revealed the paths through which light, food, and heat can entrain the circadian clock and identified that NR3C1 and FKBP/HSP90 complexes are central to the control of circadian genes through diverse environmental signals. Our study improves our understanding of the structure, design principle, and evolution of gene regulatory networks involved in the mammalian circadian rhythm

MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors

Versatile Roles of the Chromatin Remodeler CHD7 during Brain Development and Disease

CHD7 (Chromo-Helicase-DNA binding protein 7) protein is an ATP-dependent chromatin remodeler. Heterozygous mutation of the CHD7 gene causes a severe congenital disease known as CHARGE syndrome. Most CHARGE syndrome patients have brain structural anomalies, implicating an important role of CHD7 during brain development. In this review, we summarize studies dissecting developmental functions of CHD7 in the brain and discuss pathogenic mechanisms behind neurodevelopmental defects caused by mutation of CHD7. As we discussed, CHD7 protein exhibits a remarkably specific and dynamic expression pattern in the brain. Studies in human and animal models have revealed that CHD7 is involved in multiple developmental lineages and processes in the brain. Mechanistically, CHD7 is essential for neural differentiation due to its transcriptional regulation in progenitor cells

Integrative Genome-Scale Analysis Identifies Epigenetic Mechanisms of Transcriptional Deregulation in Unfavorable Neuroblastomas

The broad clinical spectrum of neuroblastoma ranges from spontaneous regression to rapid progression despite intensive multimodal therapy. This diversity is not fully explained by known genetic aberrations, suggesting the possibility of epigenetic involvement in pathogenesis. In pursuit of this hypothesis, we took an integrative approach to analyze the methylomes, transcriptomes, and copy number variations in 105 cases of neuroblastoma, complemented by primary tumor-and cell line-derived global histone modification analyses and epigenetic drug treatment in vitro. We found that DNA methylation patterns identify divergent patient subgroups with respect to survival and clinicobiologic variables, including amplified MYCN. Transcriptome integration and histone modification-based definition of enhancer elements revealed intragenic enhancer methylation as a mechanism for high-risk-associated transcriptional deregulation. Furthermore, in high-risk neuroblastomas, we obtained evidence for cooperation between PRC2 activity and DNA methylation in blocking tumor-suppressive differentiation programs. Notably, these programs could be re-activated by combination treatments, which targeted both PRC2 and DNA methylation. Overall, our results illuminate how epigenetic deregulation contributes to neuroblastoma pathogenesis, with novel implications for its diagnosis and therapy. (C) 2016 AACR