Johns Hopkins University School of Medicine

About: Johns Hopkins University School of Medicine is a healthcare organization based out in Baltimore, Maryland, United States. It is known for research contribution in the topics: Population & Cancer. The organization has 44277 authors who have published 79222 publications receiving 4788882 citations.

A mouse model for Down syndrome exhibits learning and behaviour deficits

Abstract: Trisomy 21 or Down syndrome (DS) is the most frequent genetic cause of mental retardation, affecting one in 800 live born human beings. Mice with segmental trisomy 16 (Ts65Dn mice) are at dosage imbalance for genes corresponding to those on human chromosome 21q21-22.3--which includes the so-called DS 'critical region'. They do not show early-onset of Alzheimer disease pathology; however, Ts65Dn mice do demonstrate impaired performance in a complex learning task requiring the integration of visual and spatial information. The reproducibility of this phenotype among Ts65Dn mice indicates that dosage imbalance for a gene or genes in this region contributes to this impairment. The corresponding dosage imbalance for the human homologues of these genes may contribute to cognitive deficits in DS.

Hydroxylation of HIF-1: oxygen sensing at the molecular level.

Abstract: The ability to sense and respond to changes in oxygenation represents a fundamental property of all metazoan cells. The discovery of the transcription factor HIF-1 has led to the identification of protein hydroxylation as a mechanism by which changes in Po2 are transduced to effect changes in gene expression.

Hypomethylation of DNA from benign and malignant human colon neoplasms.

Abstract: The methylation state of DNA from human colon tissue displaying neoplastic growth was determined by means of restriction endonuclease analysis. When compared to DNA from adjacent normal tissue, DNA from both benign colon polyps and malignant carcinomas was substantially hypomethylated. With the use of probes for growth hormone, gamma-globin, alpha-chorionic gonadotropin, and gamma-crystallin, methylation changes were detected in all 23 neoplastic growths examined. Benign polyps were hypomethylated to a degree similar to that in malignant tissue. These results indicate that hypomethylation is a consistent biochemical characteristic of human colonic tumors and is an alteration in the DNA that precedes malignancy.

HIF-1 and human disease: one highly involved factor

Abstract: Oxygen homeostasis represents an important organizing principle for human development and physiology. The essential requirement for oxidative phosphorylation to generate ATP is balanced by the risk of oxidative damage to cellular lipids, nucleic acids, and proteins. As a result, cellular and systemic O2 concentrations are tightly regulated via shortand long-acting response pathways that affect the activity and expression of a multitude of cellular proteins (for review, see Semenza 1999a). This delicate balance is disrupted in heart disease, cancer, cerebrovascular disease, and chronic obstructive pulmonary disease, which represent the most common causes of mortality and account for two-thirds of all deaths in the U.S. (Greenlee 2000). Appreciation of the fundamental importance of oxygen homeostasis for development, physiology, and disease pathophysiology is growing but still incomplete. Knowledge acquisition is presently exponential when one includes areas, such as the role of angiogenesis in ischemic or neoplastic disease, in which investigators are studying oxygen homeostasis even though they may not interpret their studies within this broad physiological context. Vascular endothelial growth factor (VEGF) plays an essential role in angiogenesis (for review, see Ferrara and Davis-Smyth 1997; Ferrara 1999). The regulation of VEGF expression illustrates how reduced O2 availability (hypoxia) can elicit physiological responses via multiple molecular mechanisms. VEGF expression is induced when most cell types are subjected to hypoxia, thus providing a mechanism by which tissue perfusion can be optimized to demand. Steady state levels of VEGF mRNA increase in hypoxic cells as a result of increased production (transcriptional activation) and decreased destruction (mRNA stabilization). Whereas overall protein synthesis is inhibited in response to hypoxia, VEGF mRNA is efficiently translated into protein by use of an internal ribosome entry site (Stein et al. 1998). Finally, expression of the VEGF receptor FLT-1 is also induced when endothelial cells are exposed to hypoxia (Gerber et al. 1997). The essential first step in this process, transcriptional activation, is mediated by the binding of hypoxia-inducible factor 1 (HIF-1) to a cis-acting hypoxia-response element located 1 kb 5 to the transcriptional start site of the human VEGF gene (Forsythe et al. 1996). HIF-1 is a basic helix–loop–helix PAS protein consisting of HIF-1 and HIF-1 subunits (Wang and Semenza 1995; Wang et al. 1995). HIF-1 expression and HIF-1 transcriptional activity are precisely regulated by cellular O2 concentration (for review, see Semenza 1999b, 2000a; Wenger 2000). The molecular mechanisms of sensing and signal transduction by which changes in O2 concentration result in changes in HIF-1 activity are poorly understood, but recent data suggest that the O2 signal is converted to a redox signal (Chandel et al. 2000; Haddad et al. 2000) that may trigger a kinase cascade and/or regulate HIF-1 directly (for review, see Semenza 1999a,b; Chandel and Schumacker 2000). The regulation of HIF-1 activity occurs at multiple levels. Whereas HIF-1 mRNA is constitutively expressed in tissue culture cells, it is markedly induced by hypoxia or ischemia in vivo (Yu et al. 1998; Bergeron et al. 1999). HIF-1 protein expression is negatively regulated in nonhypoxic cells by ubiquitination and proteasomal degradation (Salceda and Caro 1997; Huang et al. 1998; Kallio et al. 1999). Under hypoxic conditions, HIF-1 protein levels increase dramatically and the fraction that is ubiquitinated decreases (Sutter et al. 2000). Nuclear localization of HIF-1 may also be induced by hypoxia (Kallio et al. 1998). The carboxy-terminal half of HIF-1 contains two transactivation domains that are also negatively regulated under nonhypoxic conditions (Jiang et al. 1997b; Pugh et al. 1997). The interaction of these domains with the coactivators CBP, p300, SRC-1, and TIF2 is regulated by the cellular O2 concentration and redox state (Kallio et al. 1998; Ema et al. 1999; Carrero et al. 2000). Finally, species–specific alternative splicing of human and mouse HIF-1 RNA has also been reported (Wenger et al. 1997; Iyer et al. 1998b; Gothie et al. 2000). Hypoxia results in the rapid accumulation of HIF-1 in the nucleus (Wang et al. 1995) where it dimerizes with HIF-1 and binds to the core DNA sequence 5 -RCGTG3 (Semenza 2000a), leading to the transcriptional activation of VEGF and several dozen other known target genes (Table 1). HIF-1 and HIF-1 expression are required for embryonic survival in mice (Kozak et al. 1997; Maltepe et al. 1997; Iyer et al. 1998a; Ryan et al. 1998; 1E-MAIL gsemenza@jhmi.edu; FAX (410) 955-0484.

Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis

Abstract: Epigenetic mechanisms integrate genetic and environmental causes of disease, but comprehensive genome-wide analyses of epigenetic modifications have not yet demonstrated robust association with common diseases. Using Illumina HumanMethylation450 arrays on 354 anti-citrullinated protein antibody-associated rheumatoid arthritis cases and 337 controls, we identified two clusters within the major histocompatibility complex (MHC) region whose differential methylation potentially mediates genetic risk for rheumatoid arthritis. To reduce confounding factors that have hampered previous epigenome-wide studies, we corrected for cellular heterogeneity by estimating and adjusting for cell-type proportions in our blood-derived DNA samples and used mediation analysis to filter out associations likely to be a consequence of disease. Four CpGs also showed an association between genotype and variance of methylation. The associations for both clusters replicated at least one CpG (P < 0.01), with the rest showing suggestive association, in monocyte cell fractions in an independent cohort of 12 cases and 12 controls. Thus, DNA methylation is a potential mediator of genetic risk.