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Cabianca D.S.,Vita-Salute San Raffaele University | Cabianca D.S.,San Raffaele Scientific Institute | Gabellini D.,San Raffaele Scientific Institute | Gabellini D.,Dulbecco Telethon Institute
Journal of Cell Biology | Year: 2010

In humans, copy number variations (CNVs) are a common source of phenotypic diversity and disease susceptibility. Facioscapulohumeral muscular dystrophy (FSHD) is an important genetic disease caused by CNVs. It is an autosomal-dominant myopathy caused by a reduction in the copy number of the D4Z4 macrosatellite repeat located at chromosome 4q35. Interestingly, the reduction of D4Z4 copy number is not sufficient by itself to cause FSHD. A number of epigenetic events appear to affect the severity of the disease, its rate of progression, and the distribution of muscle weakness. Indeed, recent findings suggest that virtually all levels of epigenetic regulation, from DNA methylation to higher order chromosomal architecture, are altered at the disease locus, causing the de-regulation of 4q35 gene expression and ultimately FSHD. © 2010 Cabianca and Gabellini.


Cabianca D.S.,San Raffaele Scientific Institute | Casa V.,San Raffaele Scientific Institute | Casa V.,Vita-Salute San Raffaele University | Bodega B.,University of Milan | And 5 more authors.
Cell | Year: 2012

Repetitive sequences account for more than 50% of the human genome. Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease associated with reduction in the copy number of the D4Z4 repeat mapping to 4q35. By an unknown mechanism, D4Z4 deletion causes an epigenetic switch leading to de-repression of 4q35 genes. Here we show that the Polycomb group of epigenetic repressors targets D4Z4 in healthy subjects and that D4Z4 deletion is associated with reduced Polycomb silencing in FSHD patients. We identify DBE-T, a chromatin-associated noncoding RNA produced selectively in FSHD patients that coordinates de-repression of 4q35 genes. DBE-T recruits the Trithorax group protein Ash1L to the FSHD locus, driving histone H3 lysine 36 dimethylation, chromatin remodeling, and 4q35 gene transcription. This study provides insights into the biological function of repetitive sequences in regulating gene expression and shows how mutations of such elements can influence the progression of a human genetic disease. © 2012 Elsevier Inc.


Gomes L.C.,Dulbecco Telethon Institute | Gomes L.C.,Venetian Institute of Molecular Medicine | Gomes L.C.,University of Coimbra | Benedetto G.D.,Venetian Institute of Molecular Medicine | And 4 more authors.
Nature Cell Biology | Year: 2011

A plethora of cellular processes, including apoptosis, depend on regulated changes in mitochondrial shape and ultrastructure. The role of mitochondria and of their morphology during autophagy, a bulk degradation and recycling process of eukaryotic cells constituents, is not well understood. Here we show that mitochondrial morphology determines the cellular response to macroautophagy. When autophagy is triggered, mitochondria elongate in vitro and in vivo. During starvation, cellular cyclic AMP levels increase and protein kinase A (PKA) is activated. PKA in turn phosphorylates the pro-fission dynamin-related protein 1 (DRP1), which is therefore retained in the cytoplasm, leading to unopposed mitochondrial fusion. Elongated mitochondria are spared from autophagic degradation, possess more cristae, increased levels of dimerization and activity of ATP synthase, and maintain ATP production. Conversely, when elongation is genetically or pharmacologically blocked, mitochondria consume ATP, precipitating starvation-induced death. Thus, regulated changes in mitochondrial morphology determine the fate of the cell during autophagy. © 2011 Macmillan Publishers Limited. All rights reserved.


Sandri M.,University of Padua | Sandri M.,Dulbecco Telethon Institute | Sandri M.,Venetian Institute of Molecular Medicine
FEBS Letters | Year: 2010

Muscle mass represents 40-50% of the human body and, in mammals, is one of the most important sites for the control of metabolism. Moreover, during catabolic conditions, muscle proteins are mobilized to sustain gluconeogenesis in the liver and to provide alternative energy substrates for organs. However, excessive protein degradation in the skeletal muscle is detrimental for the economy of the body and it can lead to death. The ubiquitin-proteasome and autophagy-lysosome systems are the major proteolytic pathways of the cell and are coordinately activated in atrophying muscles. However, the role and regulation of the autophagic pathway in skeletal muscle is still largely unknown. This review will focus on autophagy and discuss its beneficial or detrimental role for the maintenance of muscle mass. © 2010 Federation of European Biochemical Societies.


Sandri M.,University of Padua | Sandri M.,Dulbecco Telethon Institute | Sandri M.,Venetian Institute of Molecular Medicine
American Journal of Physiology - Cell Physiology | Year: 2010

Loss of muscle mass aggravates a variety of diseases, and understanding the molecular mechanisms that control muscle wasting is critical for developing new therapeutic approaches. Weakness is caused by loss of muscle proteins, and recent studies have underlined a major role for the autophagy-lysosome system in regulating muscle mass. Some key components of the autophagy machinery are transcriptionally upregulated during muscle wasting, and their induction precedes muscle loss. However, it is unclear whether autophagy is detrimental, causing atrophy, or beneficial, promoting survival during catabolic conditions. This review discusses recent findings on signaling pathways regulating autophagy. Copyright © 2010 the American Physiological Society.


Lanzuolo C.,Dulbecco Telethon Institute | Lanzuolo C.,CNR Institute of Neurobiology and Molecular Medicine | Sardo F.L.,Dulbecco Telethon Institute | Diamantini A.,Cervello | Orlando V.,Dulbecco Telethon Institute
PLoS Genetics | Year: 2011

Polycomb group (PcG) proteins are part of a conserved cell memory system that conveys epigenetic inheritance of silenced transcriptional states through cell division. Despite the considerable amount of information about PcG mechanisms controlling gene silencing, how PcG proteins maintain repressive chromatin during epigenome duplication is still unclear. Here we identified a specific time window, the early S phase, in which PcG proteins are recruited at BX-C PRE target sites in concomitance with H3K27me3 repressive mark deposition. Notably, these events precede and are uncoupled from PRE replication timing, which occurs in late S phase when most epigenetic signatures are reduced. These findings shed light on one of the key mechanisms for PcG-mediated epigenetic inheritance during S phase, suggesting a conserved model in which the PcG-dependent H3K27me3 mark is inherited by dilution and not by de novo methylation occurring at the time of replication. © 2011 Lanzuolo et al.


More L.,Dulbecco Telethon Institute | Jensen G.,Columbia University
Learning and Memory | Year: 2014

Forty mice acquired conditioned responses to stimuli presented in a multiple schedule with variable inter-trial intervals (ITIs). In some trials, reinforcement was preceded by a variable conditioned stimulus (CS), while other trials were reinforced following distinctive fixed-duration CS. A third stimulus was presented but never paired with reinforcement. Subjects in five groups experienced ITIs of different durations. Acquisition of responding to each stimulus depended only on the cycle-totrial ratio (C/T), and thus on the temporal contingency of each stimulus. Acquisition was unaffected by whether CSs were of fixed or variable duration. © 2014 Morè and Jensen.


Lanzuolo C.,Dulbecco Telethon Institute | Lanzuolo C.,2CNR Institute of Cell Biology and Neurobiology | Orlando V.,Dulbecco Telethon Institute
Annual Review of Genetics | Year: 2012

The first genes composing the Polycomb group (PcG) were identified 50 years ago in Drosophila melanogaster as essential developmental functions that regulate the correct segmental expression of homeotic selector genes. In the past two decades, what was initially described as a large family of chromatin-associated proteins involved in the maintenance of transcriptional repression to maintain cellular memory of homeotic genes turned out to be a highly conserved and sophisticated network of epigenetic regulators that play key roles in multiple aspects of cell physiology and identity, including regulation of all developmental genes, cell differentiation, stem and somatic cell reprogramming and response to environmental stimuli. These myriad phenotypes further spread interest for the contribution that PcG proteins revealed in the pathogenesis and progression of cancer and other complex diseases. Recent novel insights have increasingly clarified the molecular regulatory mechanisms at the basis of PcG-mediated epigenetic silencing and opened new visions about PcG functions in cells. In this review, we focus on the multiple modes of action of the PcG complexes and describe their biological roles. © 2012 by Annual Reviews.


Fanelli F.,Dulbecco Telethon Institute | Felline A.,Dulbecco Telethon Institute
Biochimica et Biophysica Acta - Biomembranes | Year: 2011

G protein Coupled Receptors (GPCRs) are allosteric proteins whose functioning fundamentals are the communication between the two poles of the helix bundle. The representation of GPCR structures as networks of interacting amino acids can be a meaningful way to decipher the impact of ligand and of dimerization/oligomerization on the molecular communication intrinsic to the protein fold. In this study, we predicted likely homodimer architectures of the A 2AR and investigated the effects of dimerization on the structure network and the communication paths of the monomeric form. The results of this study emphasize the roles of helix 1 in A 2AR dimerization and of highly conserved amino acids in helices 1, 2, 6 and 7 in maintaining the structure network of the A 2AR through a persistent hub behavior as well as in the information flow between the extracellular and intracellular poles of the helix bundle. The arginine of the conserved E/DRY motif, R3.50, is not involved in the communication paths but participates in the structure network as a stable hub, being linked to both D3.49 and E6.30 like in the inactive states of rhodopsin. A 2AR dimerization affects the communication networks intrinsic to the receptor fold in a way dependent on the dimer architecture. Certain architectures retain the most recurrent communication paths with respect to the monomeric antagonist-bound form but enhancing path numbers and frequencies, whereas some others impair ligand-mediated communication networks. Ligand binding affects the network as well. Overall, the communication network that pertains to the functional dynamics of a GPCR is expected to be influenced by ligand functionality, oligomeric order and architecture of the supramolecular assembly. This article is part of a Special Issue entitled: "Adenosine Receptors". © 2010 Elsevier B.V.


Fanelli F.,Dulbecco Telethon Institute | Seeber M.,Dulbecco Telethon Institute
FASEB Journal | Year: 2010

Disease-causing missense mutations in membrane proteins, such as rhodopsin mutations associated with the autosomal dominant form of retinitis pigmentosa (ADRP), are often linked to defects in folding and/or trafficking. The mechanical unfolding of wild-type rhodopsin was compared with that of 20 selected ADRP-linked mutants more or less defective in folding and retinal binding. Rhodopsin fold is characterized by networks of amino acids in the retinal and G-protein binding sites likely to play a role in the stability and function of the protein. The distribution of highly connected nodes in the network reflects the existence of a diffuse intramolecular communication inside and between the 2 poles of the helix bundle, which makes pathogenic mutations share similar phenotypes irrespective of topological and physicochemical differences between them. Because of this communication, the ADRP-linked rhodopsin mutations share a more or less marked ability to impair selected hubs in the protein structure network. The extent of this structural effect relates to the severity of the biochemical defect caused by mutation. The investigative strategy employed in this study is likely to apply to all structurally known membrane proteins particularly susceptible to misassembly-causing mutations. © FASEB.

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