Transcriptional activators, several different coactivators, and general transcription factors are necessary to access specific loci in the dense chromatin structure to allow precise initiation of RNA polymerase II (Pol II) transcription. Histone acetyltransferase (HAT) complexes were implicated in loosening the chromatin around promoters and thus in gene activation. Here we demonstrate that the 2 MDa GCN5 HAT-containing metazoan TFTC/STAGA complexes contain a histone H2A and H2B deubiquitinase activity. We have identified three additional subunits of TFTC/STAGA (ATXN7L3, USP22, and ENY2) that form the deubiquitination module. Importantly, we found that this module is an enhancer of position effect variegation in Drosophila. Furthermore, we demonstrate that ATXN7L3, USP22, and ENY2 are required as cofactors for the full transcriptional activity by nuclear receptors. Thus, the deubiquitinase activity of the TFTC/STAGA HAT complex is necessary to counteract heterochromatin silencing and acts as a positive cofactor for activation by nuclear receptors in vivo.

The SAGA (Spt-Ada-Gcn5 acetyltransferase) coactivator complex contains distinct chromatin-modifying activities and is recruited by DNA-bound activators to regulate the expression of a subset of genes. Surprisingly, recent studies revealed little overlap between genome-wide SAGA-binding profiles and changes in gene expression upon depletion of subunits of the complex. As indicators of SAGA recruitment on chromatin, we monitored in yeast and human cells the genome-wide distribution of histone H3K9 acetylation and H2B ubiquitination, which are respectively deposited or removed by SAGA. Changes in these modifications after inactivation of the corresponding enzyme revealed that SAGA acetylates the promoters and deubiquitinates the transcribed region of all expressed genes. In agreement with this broad distribution, we show that SAGA plays a critical role for RNA polymerase II recruitment at all expressed genes. In addition, through quantification of newly synthesized RNA, we demonstrated that SAGA inactivation induced a strong decrease of mRNA synthesis at all tested genes. Analysis of the SAGA deubiquitination activity further revealed that SAGA acts on the whole transcribed genome in a very fast manner, indicating a highly dynamic association of the complex with chromatin. Thus, our study uncovers a new function for SAGA as a bone fide cofactor for all RNA polymerase II transcription.

Abstract-Recent studies have shown that large-artery wall remodeling per se does not reduce distensibility in hypertension, indicating qualitative or quantitative changes in arterial components. The aim of the study was to determine in 1-year-old spontaneously hypertensive rats (SHRs) the changes in the elastic properties of large arteries, as assessed by the incremental elastic modulus (E inc ), and the changes in the extracellular matrix, including fibronectin (FN) and ␣5␤1-integrin. The relationship between E inc and circumferential wall stress was calculated from in vivo pulsatile changes in blood pressure and arterial diameter by using a high-resolution echo-tracking system at the site of the abdominal aorta and in vitro medial cross-sectional area. E inc -stress curves and FN and integrin ␣5-subunit contents were determined for each animal. Mean stress and E inc were higher in SHRs than in Wistar rats. However, in a common range of stress, E inc -stress curves for SHRs were superimposable on those for Wistar rats, indicating that wall materials in both strains have equivalent mechanical behavior. Immunohistochemistry indicated that total FN, EIIIA FN isoform, and ␣5-integrin increased in the SHRs aortas without changes in elastin and collagen densities. Key Words: SHR Ⅲ elastic modulus Ⅲ aorta Ⅲ fibronectin Ⅲ ␣5␤1-integrin T he mechanical properties of large arteries play a major role in cardiovascular hemodynamics through the buffering of stroke volume and the propagation of the pressure pulse.1,2 It is well recognized that mechanical properties of large arteries are primarily determined by the composition of the arterial wall. The ECM proteins, mainly collagen and elastin, influence the "passive" mechanical properties of the arterial wall whereas its "active" properties depend on the activation of VSMCs.It was generally accepted that hypertension produced an increase in large-artery stiffness.1-4 However, recent studies have shown that arterial stiffness is not increased, despite wall hypertrophy, in either hypertensive patients or SHRs. [5][6][7][8][9] This finding suggests that sustained hypertension is associated with a rearrangement of the arterial wall material, implying qualitative or quantitative changes in arterial components leading to the mechanical adaptation of the arterial wall.The elastic properties of the arterial wall material depend not only on the SMC, elastin, and collagen contents but also on the way these components are spatially organized within the media. 3,10,11 Through an interaction with specific cellular integrin receptors, FN plays an important role in cell-matrix interactions. In addition, FN may also influence VSMC phenotype.12-14 The present study was undertaken to relate the changes in the elastic properties of the arterial wall material to its composition in the ECM and to focus on FN and its specific receptor, the ␣5␤1-integrin.The interaction of specific ECM proteins with their integrin receptors has been shown to play a central role in transmitting mechanical forces to...