Biomedical subjects

Slimane Ait-Si-Ali

Publications and source records attributed to Slimane Ait-Si-Ali.

10 recordsLinked to original sources

PubMed2006

The histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity.

The histone variant mH2A is believed to be involved in transcriptional repression, but how it exerts its function remains elusive. By using chromatin immunoprecipitation and tandem affinity immunopurification of the mH2A1.1 nucleosome complex, we identified numerous genes with promoters containing mH2A1.1 nucleosomes. In particular, the promoters of the inducible Hsp70.1 and Hsp70.2 genes, but not that of the constitutively expressed Hsp70.8, were highly enriched in mH2A1.1. PARP-1 was identified as a part of the mH2A1.1 nucleosome complex and was found to be associated with the Hsp70.1 promoter. A specific interaction between mH2A1.1 and PARP-1 was demonstrated and found to be associated with inactivation of PARP-1 enzymatic activity. Heat shock released both mH2A1.1 and PARP-1 from the Hsp70.1 promoter and activated PARP-1 automodification activity. The data we present point to a novel mechanism for control of Hsp70.1 gene transcription. mH2A1.1 recruits PARP-1 to the promoter, thereby inactivating it. Upon heat shock, the Hsp70.1 promoter-bound PARP-1 is released to activate transcription through ADP-ribosylation of other Hsp70.1 promoter-bound proteins.

Chromatin↗

PubMed2006

Acetylation is important for MyoD function in adult mice.

Acetylation is a post-translational modification that influences the activity of numerous proteins in vitro. Among them, the myogenic transcription factor MyoD shows an increased transcriptional activity in vitro when acetylated on two lysines (K): lysines 99 and 102. Here, we have investigated the biological relevance of this acetylation in vivo. Using specific antibodies, we show that endogenous MyoD is acetylated on lysines 99 and 102 in myoblasts. Moreover, we show the functional importance of acetylation in live animals by using a mutant of MyoD in which lysines 99 and 102 were replaced by arginines (R). Knock-in embryos homozygous for the MyoD(R99,102) allele expressed slightly reduced levels of MyoD but developed normally. However, the knock-in homozygous adult mice showed a phenotype that was almost identical to that of MyoD-knockout animals, including delayed muscle regeneration in vivo and an increased number of myoblasts but with reduced differentiation potential in vitro. Together, these results show the importance of MyoD acetylation for adult myogenesis.

Acetylation↗

PubMed2006

The microRNA miR-181 targets the homeobox protein Hox-A11 during mammalian myoblast differentiation.

Deciphering the mechanisms underlying skeletal muscle-cell differentiation in mammals is an important challenge. Cell differentiation involves complex pathways regulated at both transcriptional and post-transcriptional levels. Recent observations have revealed the importance of small (20-25 base pair) non-coding RNAs (microRNAs or miRNAs) that are expressed in both lower organisms and in mammals. miRNAs modulate gene expression by affecting mRNA translation or stability. In lower organisms, miRNAs are essential for cell differentiation during development; some miRNAs are involved in maintenance of the differentiated state. Here, we show that miR-181, a microRNA that is strongly upregulated during differentiation, participates in establishing the muscle phenotype. Moreover, our results suggest that miR-181 downregulates the homeobox protein Hox-A11 (a repressor of the differentiation process), thus establishing a functional link between miR-181 and the complex process of mammalian skeletal-muscle differentiation. Therefore, miRNAs can be involved in the establishment of a differentiated phenotype - even when they are not expressed in the corresponding fully differentiated tissue.

Animals↗

PubMed2006

Chromatin modification and muscle differentiation.

Skeletal muscle differentiation is a multistep process, which begins with the commitment of multi-potent mesodermal precursor cells to the muscle fate. These committed cells, the myoblasts, then differentiate and fuse into multinucleated myotubes. The final step of muscle differentiation is the maturation of differentiated myotubes into myofibres. Skeletal muscle development requires the coordinated expression of various transcription factors like the members of the myocyte enhancer binding-factor 2 family and the muscle regulatory factors. These transcription factors, in collaboration with chromatin-remodelling complexes, act in specific combinations and within complex transcriptional regulatory networks to achieve skeletal myogenesis. Additional factors involved in the epigenetic regulation of this process continue to be discovered. In this review, the authors discuss the recent discoveries in the epigenetic regulation of myogenesis. They also summarise the role of chromatin-modifying enzymes regulating muscle gene expression. These different factors are often involved in multiple steps of muscle differentiation and have redundant activities. Altogether, the recent findings have allowed a better understanding of myogenesis and have raised new hopes for the pharmacological development of new therapies aimed at muscle degeneration diseases, such as myotonic dystrophy or Duchenne muscular dystrophy.

Animals↗

PubMed2005

Nuclear positioning, gene activity and cancer.

In the interphasic nucleus, chromosomes are non-randomly arranged within the nuclear space. Indeed, chromosomes are thought to be organised into "chromosome territories". The size of a chromosome territory is roughly determined by its DNA content, but is also influenced by other factors, such as their transcriptional status. Chromatin modifications and positioning of genetic loci in the nucleus play a critical role in the control of gene expression. Emerging evidence suggests that the nucleus is structurally and functionally compartimentalized and desorganization of such a structure might play a major role in the emergence of human diseases such as cancer.

Cell Nucleus↗

PubMed2005

siRNA as a route to new cancer therapies.

The RNA interference (RNAi) gene-silencing mechanism is induced by double-stranded RNA (dsRNA) and is highly sequence-specific. It is an extremely powerful tool for silencing gene expression in vitro, and might be used as therapy in human pathologies such as cancer, viral infections and genetic disorders. RNAi was initially discovered in plants, but it has become clear that it is also conserved in animal species. Triggering of RNAi by the introduction of small dsRNA (or small interfering RNA) into living cells as a tool to inhibit the expression of specific genes holds the promise to selectively extinguish the expression of disease-associated genes in humans. On the other hand, RNAi technology will serve to elucidate the functions and interactions of the thousands of human genes in high-throughput systems and help in target validation technology.

Animals↗

PubMed2004

Chromatin dynamics and cancer.

Chomatin remodeling multi-protein complexes play a key regulatory role in many physiological processes such proliferation and differentiation. The alteration in the recruitment or in the function of one of these chromatin remodeling factors can lead to a proliferation defect, that might result from the aberrant activation or repression of key genes that regulate cell proliferation. In fact, aberrant chromatin remodeling leads to severe human diseases such as leukemia, epithelial cancers and Rubinstein-Taybi syndrome.

Adenosine Triphosphate↗

PubMed2004

A Suv39h-dependent mechanism for silencing S-phase genes in differentiating but not in cycling cells.

The Rb/E2F complex represses S-phase genes both in cycling cells and in cells that have permanently exited from the cell cycle and entered a terminal differentiation pathway. Here we show that S-phase gene repression, which involves histone-modifying enzymes, occurs through distinct mechanisms in these two situations. We used chromatin immunoprecipitation to show that methylation of histone H3 lysine 9 (H3K9) occurs at several Rb/E2F target promoters in differentiating cells but not in cycling cells. Furthermore, phenotypic knock-down experiments using siRNAs showed that the histone methyltransferase Suv39h is required for histone H3K9 methylation and subsequent repression of S-phase gene promoters in differentiating cells, but not in cycling cells. These results indicate that the E2F target gene permanent silencing mechanism that is triggered upon terminal differentiation is distinct from the transient repression mechanism in cycling cells. Finally, Suv39h-depleted myoblasts were unable to express early or late muscle differentiation markers. Thus, appropriately timed H3K9 methylation by Suv39h seems to be part of the control switch for exiting the cell cycle and entering differentiation.

Animals↗

PubMed2004

[RNA interference and its possible use in cancer therapy].

Post-transcriptional gene silencing (PTGS) or RNA interference (RNAi) is a powerful tool for silencing gene expression. This mechanism was initially considered as a strange phenomenon limited to few plant species. It has become clear that PTGS occurs in both plants and animals and has roles in viral defense and transposon silencing mechanisms. However, the use of RNA interference triggered by the introduction of small double-stranded RNA (dsRNA or siRNA) into mammalian cells as a tool to knock down expression of specific genes holds the promise to selectively inhibit expression of disease-associated genes in humans. On the other hand, there are about 40,000 protein-coding genes in the human genome, but the function of most of them remains unknown. RNAi technology has now been developed for systematically deciphering the functions and interactions of these thousands of genes.

Animals↗

PubMed2003

SiRNA-mediated inhibition of vascular endothelial growth factor severely limits tumor resistance to antiangiogenic thrombospondin-1 and slows tumor vascularization and growth.

In the past few years, several laboratories have developed antiangiogenic molecules that starve tumors by targeting their vasculature and we have shown that, when produced in tumors, the antiangiogenic molecule thrombospondin-1 (TSP1) reduces the vascularization and delays tumor onset. Yet over time, tumor cells producing active TSP1 do eventually form exponentially growing tumors. These tumors are composed of cells secreting unusually high amounts of the angiogenic stimulator vascular endothelial growth factor (VEGF) that are sufficient to overcome the inhibitory TSP1. Here, we use short double-stranded RNA (siRNA) to trigger RNA interference and thereby impair the synthesis of VEGF and ask if this inability to produce VEGF prevents the development of TSP1 resistance. Systemic in vivo administration of crude anti-VEGF siRNA reduced the growth of unaltered fibrosarcoma tumor cells, and when the anti-VEGF siRNA was expressed from tumor cells themselves, such inhibition was synergistic with the inhibitory effects derived from TSP1 secretion by the tumor cells. Anti-VEGF siRNA delayed the emergence of TSP1-resistant tumors and strikingly reduced their subsequent growth rate.

Animals↗