ABSTRACT
Wilms tumor is the most common pediatric kidney cancer. To identify transcriptional and epigenetic mechanisms that drive this disease, we compared genome-wide chromatin profiles of Wilms tumors, embryonic stem cells (ESCs), and normal kidney. Wilms tumors prominently exhibit large active chromatin domains previously observed in ESCs. In the cancer, these domains frequently correspond to genes that are critical for kidney development and expressed in the renal stem cell compartment. Wilms cells also express "embryonic" chromatin regulators and maintain stem cell-like p16 silencing. Finally, Wilms and ESCs both exhibit "bivalent" chromatin modifications at silent promoters that may be poised for activation. In Wilms tumor, bivalent promoters correlate to genes expressed in specific kidney compartments and point to a kidney-specific differentiation program arrested at an early-progenitor stage. We suggest that Wilms cells share a transcriptional and epigenetic landscape with a normal renal stem cell, which is inherently susceptible to transformation and may represent a cell of origin for this disease.
Subject(s)
Chromatin/metabolism , Kidney Neoplasms/genetics , Kidney/metabolism , Neoplasm Proteins/metabolism , Wilms Tumor/genetics , Adaptor Proteins, Signal Transducing , Cell Differentiation/genetics , Cell Transformation, Neoplastic/genetics , Chromatin/genetics , Chromatin Immunoprecipitation , Cyclin-Dependent Kinase Inhibitor p16 , DNA Methylation , Embryonic Stem Cells/metabolism , Embryonic Stem Cells/pathology , Gene Expression Regulation, Developmental , Gene Regulatory Networks , Genome-Wide Association Study , Humans , Kidney/pathology , Kidney Neoplasms/pathology , Kidney Neoplasms/physiopathology , Mutation/genetics , Neoplasm Proteins/genetics , Organ Specificity , Transcription, Genetic , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/genetics , Wilms Tumor/pathology , Wilms Tumor/physiopathologyABSTRACT
The role of the Mg2+ cation on antihypertensive molecule binding on human serum albumin (HSA) was studied by affinity chromatography. The thermodynamic data corresponding to this binding were determined for a wide range of Mg2+ concentrations (c). For the nifedipine molecule, an increase in the Mg2+ concentration produced a decrease in binding due to a decrease in the electrostatic interactions. For verapamil and diltiazem, which have the highest solvent accessible surface area, the solute binding on HSA was divided into two Mg2+ concentration regions. For a low c value below c(c) (approximately 1.6 mmol/l), the binding dependence with c was similar to that of nifedipine. For c above c(c) the hydrophobic effect created in the bulk solvent associated with a decrease in the van der Waals interactions between the solute molecule and the HSA implied a decrease in its binding. These results showed that for patients with hypertension, an Mg2+ supplementation during treatment with these antihypertensive molecules can increase the active pharmacological molecule concentration.