Extensive changes in posttranslational histone modifications accompany the rewiring of the transcriptional program during stem cell differentiation. However, the mechanisms controlling the changes in specific chromatin modifications and their function during differentiation remain only poorly understood. We show that histone H2B monoubiquitination (H2Bub1) significantly increases during differentiation of human mesenchymal stem cells (hMSCs) and various lineage-committed precursor cells and in diverse organisms. Furthermore, the H2B ubiquitin ligase RNF40 is required for the induction of differentiation markers and transcriptional reprogramming of hMSCs. This function is dependent upon CDK9 and the WAC adaptor protein, which are required for H2B monoubiquitination. Finally, we show that RNF40 is required for the resolution of the H3K4me3/H3K27me3 bivalent poised state on lineage-specific genes during the transition from an inactive to an active chromatin conformation. Thus, these data indicate that H2Bub1 is required for maintaining multipotency of hMSCs and plays a central role in controlling stem cell differentiation.

Mitochondria occupy a central position in cellular metabolism. Their protein complement must therefore be dynamically adjusted to the metabolic demands of the cell. As >95% of mitochondrial proteins are encoded by nuclear DNA, regulation of the mitochondrial proteome requires signals that sense the status of the organelle and communicate it back to the nucleus. This is referred to as retrograde signalling. Mitochondria are tightly integrated into the network of cellular processes, and the output of mitochondrial retrograde signalling therefore not only feeds back to the mitochondrion, but also regulates functions across the cell. A number of transcriptomic studies have assessed the role of retrograde signalling in plants. However, single studies of a specific mitochondrial dysfunction may also measure secondary effects in addition to the specific transcriptomic output of mitochondrial signals. To gain an improved understanding of the output and role of mitochondrial retrograde signalling, a meta-analysis of 11 transcriptomic data sets from different models of plant mitochondrial dysfunction was performed. Comparing microarray data from stable mutants and short-term chemical treatments revealed unique features and commonalities in the responses that are under mitochondrial retrograde control. In particular, a common regulation of transcripts of the following functional categories was observed: plant-pathogen interactions, protein biosynthesis, and light reactions of photosynthesis. The possibility of a novel mode of interorganellar signalling, in which the mitochondrion influences processes in the plastid and other parts of the cell, is discussed.

Previously, we have identified the transcription factor CUTL1 as an important mediator of tumor invasion and target of tumor growth factor-beta. Using high-throughput approaches, we identified several putative downstream effectors of CUTL1, among them WNT5A, a secreted member of the Wnt multigene family. The aim of this study was to investigate the role of WNT5A as a novel target of CUTL1 in pancreatic cancer. CUTL1 and WNT5A were stably over-expressed as well as transiently and stably knocked down by RNA interference. Effects on proliferation, migration and invasiveness were investigated by thymidine incorporation, Boyden chamber experiments and time-lapse microscopy. Expression of WNT5A in pancreatic cancer tissues was analyzed by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. We found that CUTL1 transcriptionally up-regulated WNT5A on RNA, protein and promoter level. WNT5A significantly enhanced migration, proliferation and invasiveness, mediating the pro-invasive effects of CUTL1 to a major extent. WNT5A effects were accompanied by a marked modulation of marker genes associated with epithelial-mesenchymal transition. Using RT-PCR and immunohistochemistry, we found that WNT5A is up-regulated early during pancreatic cancerogenesis in pancreatic intraepithelial neoplasias lesions and in invasive pancreatic adenocarcinomas, as compared with normal pancreas tissues. These data identify WNT5A as important target of CUTL1 and as novel mediator of invasiveness and tumor progression in pancreatic cancer.

Ecdysteroids affect Drosophila ovarian stem cell niche formation and early germline differentiationEcdysteroids affect Drosophila ovarian stem cell niche formation and early germline differentiation. The steroid hormone ecdysone regulates germline development and stem cell niche establishment in the Drosophila ovary by modulating TGF-β signalling and cell adhesion.

The posttranslational regulation of proteins by lysine (Lys) acetylation has recently emerged to occur not only on histones, but also on organellar proteins in plants and animals. In particular, the catalytic activities of metabolic enzymes have been shown to be regulated by Lys acetylation. The Arabidopsis (Arabidopsis thaliana) genome encodes two predicted sirtuin-type Lys deacetylases, of which only Silent Information Regulator2 homolog (SRT2) contains a predicted presequence for mitochondrial targeting. Here, we have investigated the function of SRT2 in Arabidopsis. We demonstrate that SRT2 functions as a Lys deacetylase in vitro and in vivo. We show that SRT2 resides predominantly at the inner mitochondrial membrane and interacts with a small number of protein complexes mainly involved in energy metabolism and metabolite transport. Several of these protein complexes, such as the ATP synthase and the ATP/ADP carriers, show an increase in Lys acetylation in srt2 loss-of-function mutants. The srt2 plants display no growth phenotype but rather a metabolic phenotype with altered levels in sugars, amino acids, and ADP contents. Furthermore, coupling of respiration to ATP synthesis is decreased in these lines, while the ADP uptake into mitochondria is significantly increased. Our results indicate that SRT2 is important in fine-tuning mitochondrial energy metabolism.Mitochondria are central hubs of energy metabolism in plants and animals. In addition to a fine-tuned mitochondria-to-nuclear signaling that regulates transcription of nuclear gene expression (Rhoads and Subbaiah, 2007;Schwarzländer et al., 2012), posttranslational modifications of proteins are thought to be essential for the regulation of central metabolic pathways and thus determine the plasticity of plant metabolism (Hartl and Finkemeier, 2012). In mammalian mitochondria, the regulation of metabolic functions by posttranslational