e One of the most striking epigenetic alterations that occurs at the level of the nucleosome is the complete exchange of the canonical H2A histones for the macroH2A variant. Here, we provide insight into the poorly recognized function of macroH2A in transcriptional activation and demonstrate its relevance in embryonic and adult stem cells. Knockdown of macroH2A1 in mouse embryonic stem (mES) cells limited their capacity to differentiate but not their self-renewal. The loss of macroH2A1 interfered with the proper activation of differentiation genes, most of which are direct target genes of macroH2A. Additionally, macroH2A1-deficient mES cells displayed incomplete inactivation of pluripotency genes and formed defective embryoid bodies. In vivo, macroH2A1-deficient teratomas contained a massive expansion of malignant, undifferentiated carcinoma tissue. In the heterogeneous culture of primary human keratinocytes, macroH2A1 levels negatively correlated with the self-renewal capacity of the pluripotent compartment. Together these results establish macroH2A1 as a critical chromatin component that regulates the delicate balance between self-renewal and differentiation of embryonic and adult stem cells.
How metabolism and epigenetics are molecularly linked and regulate each other is poorly understood. In this review, we will discuss the role of direct metabolite-binding to chromatin components and modifiers as a possible regulatory mechanism. We will focus on globular macro domains, which are evolutionarily highly conserved protein folds that can recognize NAD(+)-derived metabolites. Macro domains are found in histone variants, histone modifiers, and a chromatin remodeler among other proteins. Here we summarize the macro domain-containing chromatin proteins and the enzymes that generate relevant metabolites. Focusing on the histone variant macroH2A, we further discuss possible implications of metabolite binding for chromatin function.
Cholesterol accumulation in Niemann-Pick type C disease (NPC) causes increased levels of the amyloid-precursor-protein C-terminal fragments (APP-CTFs) and intracellular amyloid-β peptide (Aβ), the two central molecules in Alzheimer's disease (AD) pathogenesis. We previously reported that cholesterol accumulation in NPC-cells leads to cholesterol-dependent increased APP processing by β-secretase (BACE1) and decreased APP expression at the cell surface (Malnar et al. Biochim Biophys Acta. 1802 (2010) 682-691.). We hypothesized that increased formation of APP-CTFs and Aβ in NPC disease is due to cholesterol-mediated altered endocytic trafficking of APP and/or BACE1. Here, we show that APP endocytosis is prerequisite for enhanced Aβ levels in NPC-cells. Moreover, we observed that NPC cells show cholesterol dependent sequestration and colocalization of APP and BACE1 within enlarged early/recycling endosomes which can lead to increased β-secretase processing of APP. We demonstrated that increased endocytic localization of APP in NPC-cells is likely due to both its increased internalization and its decreased recycling to the cell surface. Our findings suggest that increased cholesterol levels, such as in NPC disease and sporadic AD, may be the upstream effector that drives amyloidogenic APP processing characteristic for Alzheimer's disease by altering endocytic trafficking of APP and BACE1.
The importance of epigenetic mechanisms is most clearly illustrated during early development when a totipotent cell goes through multiple cell fate transitions to form the many different cell types and tissues that constitute the embryo and the adult. The exchange of a canonical H2A histone for the ‘repressive’ macroH2A variant is one of the most striking epigenetic chromatin alterations that can occur at the level of the nucleosome. Here, we discuss recent data on macroH2A in zebrafish and mouse embryos, in embryonic and adult stem cells and also in nuclear reprogramming. We highlight the role of macroH2A in the establishment and maintenance of differentiated states and we discuss its still poorly recognized function in transcriptional activation.
Background: Alzheimer's disease is associated with extracellular deposits of amyloid-peptides (A) in the brain. Sequential proteolytic processing of the-amyloid precursor protein (APP) by secretases leads to generation of A. APP is first cleaved by either-secretase or-secretase which releases most of ectodomain leaving behind short c-terminal fragment (APP-CTF) tethered within membrane. APP-CTF acts as substrate to-secretase to release A. Several studies have indicated dysregulation of protein transport and lipid metabolism as an important aspect of AD. Previously, we also showed that the inhibition of glycosphingolipid (GSL) biosynthesis reduces secretion of A. Sphingolipids are enriched in the plasma membrane, from here they are transported to late endocytic compartments where they are degraded. Inherited defects in degradation of these lipids cause sphingolipid storage disorders (SLSDs) marked by their accumulation in neurons and neurodegeneration. Both, AD as well as SLSDs are associated with intraneuronal tau tangles and inflammation. There is a common defect in lipid transport along the endocytic pathway in SLSDs and the processing of APP also occurs predominantly in post-Golgi secretory and endocytic compartments, therefore we investigated the effect of accumulation of sphingolipids on transport and processing of APP. Overall objective of the study was to address the common mechanisms involved in SLSDs and AD, if any. Methods: We used cultured cells and increased GSLs levels by incubation with bovine brain gangliosides. The processing of APP and its derivatives was studied by immunoblotting. Pulse chase experiments were performed to analyze the turnover of APP metabolites. Subcellular distribution of APP and its products was analysed by density gradient and immunocytochemistry. Results: The accumulation of sphingolipids markedly increased the secretion of A and lead to strong increase in APP-CTF levels. However-secretase activity was not affected by GSLs in in vitro assays. We demonstrate that the increased levels of cellular GSLs altered the distribution and stability APP-CTFs. Similar results were also obtained in independent genetic models. Conclusions: Alteration in sphingolipid metabolism with associated accumulation of APP-CTFs might underlie the pathophysiologic events in AD as well as sphingolipid storage disorders along with other reported factors. Background: A sphingolipid storage disease (SLSD) Niemann Pick type C (NPC) is caused by dysfunction of NPC1 protein which leads to accumulation of free cholesterol and glycosphingolipids in endosomal/lysoso-mal compartments. It has been recently shown that this defect leads to increased formation of amyloid-beta (Abeta) peptide, and is accompanied by altered localization of presenilin 1 to early/late endosomes. We hypothesized that cholesterol accumulation upon NPC1 loss of function leads to increased APP/C99 localization in endosomes and increased formation of Abeta in these compartments. To test this we monitored subcellular local-ization of APP/C99...
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