Chondrosarcoma is the second most common primary malignant bone tumor and is resistant to chemotherapy and radiation. Inadequate treatment response and poor prognosis requires novel therapeutic approaches. Proline‑rich polypeptide‑1 (PRP‑1), synthesized by brain neurosecretory cells, has demonstrated antitumor properties in JJ012‑cells; however, its underlying molecular mechanism remains unclear. The present study aimed to investigate the epigenetic regulation by which PRP‑1 inhibits chondrosarcoma cancer stem cell (CSC) proliferation and to elucidate additional CSC biomarkers in human chondrosarcoma other than ALDH1A1. Human chondrosarcoma JJ012‑cells were treated with PRP‑1 prior to performing an Aldefluor™ assay and fluorescence‑activated cell sorting in order to determine aldehyde dehydrogenase (ALDH) expression levels and isolate ALDHhigh and ALDHlow cell populations. ALDH is an established marker of CSCs in several neoplasms, including chondrosarcoma. The cells were collected and lysed for gel electrophoresis, followed by western blot analysis. The Aldefluor™ assay was used to assess the expression levels of well‑established CSC biomarkers, including CD133, CD4, CD10, CD144, CD177, CD221, CD271, leucine‑rich repeat‑containing G protein‑coupled receptor 5, SOX2 and B lymphoma Mo‑MLV insertion region 1 homolog (BMI‑1), within the ALDHhigh population of JJ012 cells. The results confirmed that ALDHA1 was the biomarker for chondrosarcoma CSCs. PRP‑1 was demonstrated to inhibit the ALDHhigh population colony and sarcosphere formation; 5 µg/ml PRP‑1 was indicated to be the optimum concentration in eliminating colonies formed by JJ012 cells (92%, P<0.001) and by the ALDHhigh CSC‑population (80.5%, P<0.001) in the clonogenic dose‑response assay. Spheroid growth unequivocally decreased with an increase in PRP‑1 dose. In order to determine the molecular mechanism by which PRP‑1 decreased the CSC population, the regulation of the mammalian Switch/sucrose non‑fermenting (SWI/SNF) complex, also referred to as BRG1‑associated factor (BAF) complex, which either activates or represses transcription, thus acting as an oncogene or tumor suppressor in human cells, was analyzed. PRP‑1 was demonstrated to decrease the expression levels of BRG, BAF170 and BRM; therefore, in JJ012 cells, these key players of the SWI/SNF (BAF) complex served an oncogenic role. The results of the present study demonstrated that PRP‑1 targets chromatin‑remodeling complexes; therefore, future efforts will be directed towards determining the interconnection between CSC maintenance, self‑renewal capacity and BAF complexes.

Epigenetic changes are implicated in the persisting vascular effects of hyperglycemia. The precise mechanism whereby chromatin structure and subsequent gene expression are regulated by glucose in vascular endothelial cells remain to be fully defined.
We have studied the molecular and functional mechanism whereby the Set7 methyltransferase associates with chromatin formation and histone methylation in vascular cells in response to current and previous exposure to glucose.
To characterize the molecular and functional identity of the Set7 protein, we used vascular cells overexpressing or lacking Set7. Chromatin fractionation for mono-methylation of lysine 4 on histone H3 identified methyltransferase activity. Immunofluorescence experiments strongly suggest that Set7 protein accumulates in the nucleus in response to hyperglycemia. Moreover, activation of proinflammatory genes by high glucose is dependent on Set7 but distinguished by H3K4m1 gene patterns. We show that transient hyperglycemia regulates the expression of proinflammatory genes in vascular endothelial cells in vitro and the persistent increase in glucose-induced gene expression in the aorta of nondiabetic mice.
This study uncovers that the response to hyperglycemia in vascular endothelial cells involves the H3K4 methyltransferase, Set7. This enzyme appears to regulate glucose-induced chromatin changes and gene expression not only by H3K4m1-dependent but also H3K4m1-independent pathways. Furthermore, Set7 appears to be responsible for sustained vascular gene expression in response to prior hyperglycemia and is a potential molecular mechanism for the phenomenon of hyperglycemic memory.

Regulating the transition of cells such as T lymphocytes from quiescence (G(0)) into an activated, proliferating state involves initiation of cellular programs resulting in entry into the cell cycle (proliferation), the growth cycle (blastogenesis, cell size) and effector (functional) activation. We show the first proteomic analysis of protein interaction networks activated during entry into the first cell cycle from G(0). We also provide proof of principle that blastogenesis and proliferation programs are separable in primary human T cells. We employed a proteomic profiling method to identify large-scale changes in chromatin/nuclear matrix-bound and unbound proteins in human T lymphocytes during the transition from G(0) into the first cell cycle and mapped them to form functionally annotated, dynamic protein interaction networks. Inhibiting the induction of two proteins involved in two of the most significantly upregulated cellular processes, ribosome biogenesis (eIF6) and hnRNA splicing (SF3B2/SF3B4), showed, respectively, that human T cells can enter the cell cycle without growing in size, or increase in size without entering the cell cycle.

Epigenetic histone modifications play critical roles in the control of gene transcription. Recently, an increasing number of histone H2A deubiquitinases have been identified and characterized. However, the physiological functions for this entire group of histone H2A deubiquitinases remain unknown. In this study, we revealed that the histone H2A deubiquitinase MYSM1 plays an essential and intrinsic role in early B cell development. MYSM1 deficiency results in a block in early B cell commitment and a defect of B cell progenitors in expression of EBF1 and other B lymphoid genes. We further demonstrated that MYSM1 derepresses EBF1 transcription in B cell progenitors by orchestrating histone modifications and transcription factor recruitment to the EBF1 locus. Thus, this study not only uncovers the essential role for MYSM1 in gene transcription during early B cell development but also underscores the biological significance of reversible epigenetic histone H2A ubiquitination.
Copyright © 2011 Elsevier Inc. All rights reserved.

Recent experimental evidence indicates that cardiac and chromatin remodeling are associated with changes in gene expression mediated by Brahma-related gene 1 (Brg1), a member of the large group of SWI/SNF subunits. The second catalytic member of this family is Brahma (Brm), which shares close sequence homology to Brg1. Despite the sequence similarities, these determinants are found in distinct regulatory complexes; however, the precise nature and role of these remodeling enzymes in the failing heart remains unknown. Here we have hypothesized that Brg1 and Brm form distinct complexes in regulating gene expression in an animal model of cardiac hypertrophy. We have identified that the hypertrophic myocardium is characterized by profound morphological changes associated with increased expression of ANP (Nppa), BNP (Nppb) and β-MHC (Myh7) genes, correlating with reduced expression of the α-MHC (Myh6) and SERCA2A (Atp2a2) genes. Histone deacetylase inhibition prevented left ventricular hypertrophy indicating that the re-expression of gene activity can be associated with both contextual and distinct SWI/SNF interactions. We hypothesize that cardiac hypertrophy and the fetal gene expression program are associated with distinguishable binding of Brm and Brg1 on genes present in distinct complexes, suggesting possible independent-regulatory roles.