The E1A-Associated p400 Protein Modulates Cell Fate Decisions by the Regulation of ROS Homeostasis

The p400 E1A-associated protein, which mediates H2A.Z incorporation at specific promoters, plays a major role in cell fate decisions: it promotes cell cycle progression and inhibits induction of apoptosis or senescence. Here, we show that p400 expression is required for the correct control of ROS metabolism. Depletion of p400 indeed increases intracellular ROS levels and causes the appearance of DNA damage, indicating that p400 maintains oxidative stress below a threshold at which DNA damages occur. Suppression of the DNA damage response using a siRNA against ATM inhibits the effects of p400 on cell cycle progression, apoptosis, or senescence, demonstrating the importance of ATM–dependent DDR pathways in cell fates control by p400. Finally, we show that these effects of p400 are dependent on direct transcriptional regulation of specific promoters and may also involve a positive feedback loop between oxidative stress and DNA breaks since we found that persistent DNA breaks are sufficient to increase ROS levels. Altogether, our results uncover an unexpected link between p400 and ROS metabolism and allow deciphering the molecular mechanisms largely responsible for cell proliferation control by p400

A New Isoform of the Histone Demethylase JMJD2A/KDM4A Is Required for Skeletal Muscle Differentiation

In proliferating myoblasts, muscle specific genes are silenced by epigenetic modifications at their promoters, including histone H3K9 methylation. Derepression of the promoter of the gene encoding the myogenic factor myogenin (Myog) is key for initiation of muscle differentiation. The mechanism of H3K9 demethylation at the Myog promoter is unclear, however. Here, we identify an isoform of the histone demethylase JMJD2A/KDM4A that lacks the N-terminal demethylase domain (ΔN-JMJD2A). The amount of ΔN-JMJD2A increases during differentiation of C2C12 myoblasts into myotubes. Genome-wide expression profiling and exon-specific siRNA knockdown indicate that, in contrast to the full-length protein, ΔN-JMJD2A is necessary for myotube formation and muscle-specific gene expression. Moreover, ΔN-JMJD2A promotes MyoD-induced conversion of NIH3T3 cells into muscle cells. ChIP-on-chip analysis indicates that ΔN-JMJD2A binds to genes mainly involved in transcriptional control and that this binding is linked to gene activation. ΔN-JMJD2A is recruited to the Myog promoter at the onset of differentiation. This binding is essential to promote the demethylation of H3K9me2 and H3K9me3. We conclude that induction of the ΔN-JMJD2A isoform is crucial for muscle differentiation: by directing the removal of repressive chromatin marks at the Myog promoter, it promotes transcriptional activation of the Myog gene and thus contributes to initiation of muscle-specific gene expression

REGULATIONS INTRACRINES PAR L'ISOFORME DE 210 ACIDES AMINES DU FACTEUR DE CROISSANCE FIBROBLASTIQUE HUMAIN FGF-2. IMPLICATIONS DANS L'INVASION TUMORALE ET MODULATIONS DE VOIES DE SIGNALISATION

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Methods for In Vivo Functional Studies of Chromatin-Modifying Enzymes in Early Steps of Colon Carcinogenesis

International audienc

Chromatin Dynamics in Intestinal Epithelial Homeostasis: A Paradigm of Cell Fate Determination versus Cell Plasticity

International audienceThe rapid renewal of intestinal epithelium is mediated by a pool of stem cells, located at the bottom of crypts, giving rise to highly proliferative progenitor cells, which in turn differentiate during their migration along the villus. The equilibrium between renewal and differentiation is critical for establishment and maintenance of tissue homeostasis, and is regulated by signaling pathways (Wnt, Notch, Bmp…) and specific transcription factors (TCF4, CDX2…). Such regulation controls intestinal cell identities by modulating the cellular transcriptome. Recently, chromatin modification and dynamics have been identified as major actors linking signaling pathways and transcriptional regulation in the control of intestinal homeostasis. In this review, we synthesize the many facets of chromatin dynamics involved in controlling intestinal cell fate, such as stemness maintenance, progenitor identity, lineage choice and commitment, and terminal differentiation. In addition, we present recent data underlying the fundamental role of chromatin dynamics in intestinal cell plasticity. Indeed, this plasticity, which includes dedifferentiation processes or the response to environmental cues (like microbiota's presence or food ingestion), is central for the organ's physiology. Finally, we discuss the role of chromatin dynamics in the appearance and treatment of diseases caused by deficiencies in the aforementioned mechanisms, such as gastrointestinal cancer, inflammatory bowel disease or irritable bowel syndrome

Control of genetic stability by a new heterochromatin compaction pathway involving the Tip60 histone acetyltransferase

International audienc

The H2A.Z histone variant integrates Wnt signaling in intestinal epithelial homeostasis

International audienc

Cleavage and Cytoplasmic Relocalization of Histone Deacetylase 3 Are Important for Apoptosis Progression

The apoptotic process is accompanied by major changes in chromatin structure and gene expression. The apoptotic genetic program is progressively set up with the inhibition of antiapoptotic genes and the activation of proapoptotic ones. Here, we show that the histone deacetylase 3 (HDAC-3), which is a known corepressor of many proapoptotic genes, is subjected to proteolytic cleavage during apoptosis in a cell type- and species-independent manner. This cleavage is caspase dependent and leads to the loss of the C-terminal part of HDAC-3. The cleaved form of HDAC-3 accumulates in the cytoplasm. Furthermore, we found that forced nuclear localization of HDAC-3 decreases the efficiency of apoptosis induction, indicating that HDAC-3 cytoplasmic relocalization is important for the apoptotic process. Finally, we observed that HDAC-3 cleavage allowed increased histone acetylation and transcriptional activation on a proapoptotic HDAC-3-target gene, the Fas-encoding gene. Altogether, our results thus indicate that HDAC-3 cleavage is crucial for efficient apoptosis induction because it allows the activation of some proapoptotic genes during apoptosis progression