Epigenetic regulation as a therapeutic target in the malaria parasite Plasmodium falciparum.

Over the past thirty years, epigenetic regulation of gene expression has gained increasing interest as it was shown to be implicated in illnesses ranging from cancers to parasitic diseases. In the malaria parasite, epigenetics was shown to be involved in several key steps of the complex life cycle of Plasmodium, among which asexual development and sexual commitment, but also in major biological processes like immune evasion, response to environmental changes or DNA repair. Because epigenetics plays such paramount roles in the Plasmodium parasite, enzymes involved in these regulating pathways represent a reservoir of potential therapeutic targets.

Epidrugs as Promising Tools to Eliminate Artemisinin-Resistant and Quiescent Parasites.

The use of artemisinin and its derivatives has helped reduce the burden of malaria caused by However, artemisinin-resistant parasites are able, in the presence of artemisinins, to stop their cell cycles. This quiescent state can alter the activity of artemisinin partner drugs leading to a secondary drug resistance and thus threatens malaria eradication strategies. Drugs targeting epigenetic mechanisms (namely epidrugs) are emerging as potential antimalarial drugs.

All Quiet on the TE Front? The Role of Chromatin in Transposable Element Silencing.

Transposable elements (TEs) are mobile genetic elements that constitute a sizeable portion of many eukaryotic genomes. Through their mobility, they represent a major source of genetic variation, and their activation can cause genetic instability and has been linked to aging, cancer and neurodegenerative diseases. Accordingly, tight regulation of TE transcription is necessary for normal development.

Two Isoforms of Containing Either One or Two GATA Zinc Fingers Provide Functional Diversity During Development.

GATA transcription factors play crucial roles in various developmental processes in organisms ranging from flies to humans. In mammals, GATA factors are characterized by the presence of two highly conserved domains, the N-terminal (N-ZnF) and the C-terminal (C-ZnF) zinc fingers. The GATA factor Serpent (Srp) is produced in different isoforms that contains either both N-ZnF and C-ZnF (SrpNC) or only the C-ZnF (SrpC).

A dual role of dLsd1 in oogenesis: regulating developmental genes and repressing transposons.

The histone demethylase LSD1 is a key chromatin regulator that is often deregulated in cancer. Its ortholog, dLsd1 plays a crucial role in Drosophila oogenesis; however, our knowledge of dLsd1 function is insufficient to explain its role in the ovary. Here, we have performed genome-wide analysis of dLsd1 binding in the ovary, and we document that dLsd1 is preferentially associated to the transcription start site of developmental genes.

DNA methylation signature of human hippocampus in Alzheimer's disease is linked to neurogenesis.

Background: Drawing the epigenome landscape of Alzheimer's disease (AD) still remains a challenge. To characterize the epigenetic molecular basis of the human hippocampus in AD, we profiled genome-wide DNA methylation levels in hippocampal samples from a cohort of pure AD patients and controls by using the Illumina 450K methylation arrays.

Results: Up to 118 AD-related differentially methylated positions (DMPs) were identified in the AD hippocampus, and extended mapping of specific regions was obtained by bisulfite cloning sequencing.

The LSD1 Family of Histone Demethylases and the Pumilio Posttranscriptional Repressor Function in a Complex Regulatory Feedback Loop.

The lysine (K)-specific demethylase (LSD1) family of histone demethylases regulates chromatin structure and the transcriptional potential of genes. LSD1 is frequently deregulated in tumors, and depletion of LSD1 family members causes developmental defects. Here, we report that reductions in the expression of the Pumilio (PUM) translational repressor complex enhanced phenotypes due to dLsd1 depletion in Drosophila.

The Drosophila Huntington's disease gene ortholog dhtt influences chromatin regulation during development.

Huntington's disease is an autosomal dominant neurodegenerative disorder caused by a CAG expansion mutation in HTT, the gene encoding huntingtin. Evidence from both human genotype-phenotype relationships and mouse model systems suggests that the mutation acts by dysregulating some normal activity of huntingtin. Recent work in the mouse has revealed a role for huntingtin in epigenetic regulation during development.

The emerging roles for histone demethylases in the modulation of signaling pathways.

Since their discovery in 2004, histone demethylases have emerged as key regulators of chromatin. Recent studies have started to reveal the interconnections between histone demethylases and signaling pathways, suggesting that this interplay drives fundamental biological processes. Here, we summarize the different families and subfamilies of histone demethylases and the insights into the biological roles of these enzymes that have been provided by the analysis of mutant animals.

A SIRT1-LSD1 corepressor complex regulates Notch target gene expression and development.

Epigenetic regulation of gene expression by histone-modifying corepressor complexes is central to normal animal development. The NAD(+)-dependent deacetylase and gene repressor SIRT1 removes histone H4K16 acetylation marks and facilitates heterochromatin formation. However, the mechanistic contribution of SIRT1 to epigenetic regulation at euchromatic loci and whether it acts in concert with other chromatin-modifying activities to control developmental gene expression programs remain unclear.

Functional antagonism between histone H3K4 demethylases in vivo.

Dynamic regulation of histone modifications is critical during development, and aberrant activity of chromatin-modifying enzymes has been associated with diseases such as cancer. Histone demethylases have been shown to play a key role in eukaryotic gene transcription; however, little is known about how their activities are coordinated in vivo to regulate specific biological processes. In Drosophila, two enzymes, dLsd1 (Drosophila ortholog of lysine-specific demethylase 1) and Lid (little imaginal discs), demethylate histone H3 at Lys 4 (H3K4), a residue whose methylation is associated with actively transcribed genes.

Identification of functional elements and regulatory circuits by Drosophila modENCODE.

To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction.

Egr-1-A Ca(2+)-regulated transcription factor.

The biosynthesis of the zinc finger transcription factor Egr-1 is stimulated by many extracellular signaling molecules including hormones, neurotransmitters, growth and differentiation factors. The Egr-1 gene represents a convergence point for many intracellular signaling cascades. An increase of the intracellular Ca(2+) concentration, by activating ionotropic or Galpha(q/11)-coupled receptors or voltage-gated L-type Ca(2+) channels, is often the prerequisite for enhanced Egr-1 gene transcription.

The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor.

Triggering receptor expressed in myeloid (TREM) cells 2, a receptor expressed by myeloid cells, osteoclasts and microglia, is known to play a protective role in bones and brain. Mutations of the receptor (or of its coupling protein, DAP12) sustain in fact a genetic disease affecting the two organs, the polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy (PLOSL or Nasu-Hakola disease). So far, specific agonist(s) of TREM2 have not been identified and its (their) transduction mechanisms are largely unknown.

Synergy-inducing chemokines enhance CCR2 ligand activities on monocytes.

The migration of monocytes to sites of inflammation is largely determined by their response to chemokines. Although the chemokine specificities and expression patterns of chemokine receptors are well defined, it is still a matter of debate how cells integrate the messages provided by different chemokines that are concomitantly produced in physiological or pathological situations in vivo. We present evidence for one regulatory mechanism of human monocyte trafficking.

E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8.

The E2F1 transcription factor can promote proliferation or apoptosis when activated, and is a key downstream target of the retinoblastoma tumour suppressor protein (pRB). Here we show that E2F1 is a potent and specific inhibitor of beta-catenin/T-cell factor (TCF)-dependent transcription, and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC)/glycogen synthase kinase-3 (GSK3)-independent manner, reducing the expression of key beta-catenin targets including c-MYC.

E2F and p53 induce apoptosis independently during Drosophila development but intersect in the context of DNA damage.

In mammalian cells, RB/E2F and p53 are intimately connected, and crosstalk between these pathways is critical for the induction of cell cycle arrest or cell death in response to cellular stresses. Here we have investigated the genetic interactions between RBF/E2F and p53 pathways during Drosophila development. Unexpectedly, we find that the pro-apoptotic activities of E2F and p53 are independent of one another when examined in the context of Drosophila development: apoptosis induced by the deregulation of dE2F1, or by the overexpression of dE2F1, is unaffected by the elimination of dp53; conversely, dp53-induced phenotypes are unaffected by the elimination of dE2F activity.

P2X(7) receptor stimulation upregulates Egr-1 biosynthesis involving a cytosolic Ca(2+) rise, transactivation of the EGF receptor and phosphorylation of ERK and Elk-1.

The P2X(7) receptor is an ATP-gated ionotropic receptor that is permeable for small cations including Ca(2+) ions. Using 293 cells expressing P2X(7) receptors, we show that the P2X(7) receptor-specific ligand 2',3'-O-(4-benzoyl-benzoyl)-ATP (BzATP) induces a signaling cascade leading to the biosynthesis of biologically active Egr-1, a zinc finger transcription factor. BzATP-triggered Egr-1 biosynthesis was attenuated by the mitogen-activated protein kinase kinase inhibitor PD98059, by BAPTA-AM, the acetoxymethylester of the cytosolic Ca(2+) chelator BAPTA, and by an epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor (AG1478).

Mutation of Drosophila Lsd1 disrupts H3-K4 methylation, resulting in tissue-specific defects during development.

Histone-tail modifications play a fundamental role in the processes that establish chromatin structure and determine gene expression. One such modification, histone methylation, was considered irreversible until the recent discovery of histone demethylases. Lsd1 was the first histone demethylase to be identified.

Human TFDP3, a novel DP protein, inhibits DNA binding and transactivation by E2F.

The two known DP proteins, TFDP1 and -2, bind E2Fs to form heterodimers essential for high affinity DNA binding and efficient transcriptional activation/repression. Here we report the identification of a new member of the DP family, human TFDP3. Despite the high degree of sequence similarity, TFDP3 is apparently distinct from TFDP1 in function.

A gradient of epidermal growth factor receptor signaling determines the sensitivity of rbf1 mutant cells to E2F-dependent apoptosis.

The inactivation of retinoblastoma (Rb) family members sensitizes cells to apoptosis. This cell death affects the development of mutant animals and also provides a critical constraint to the malignant potential of Rb mutant tumor cells. The extent of apoptosis caused by the inactivation of Rb is highly cell type and tissue specific, but the underlying reasons for this variation are poorly understood.

Up-regulation of tyrosine hydroxylase gene transcription by tetradecanoylphorbol acetate is mediated by the transcription factors Ets-like protein-1 (Elk-1) and Egr-1.

Tyrosine hydroxylase is the rate-limiting enzyme in the biosynthesis of catecholamines. Expression of the tyrosine hydroxylase gene is regulated at the transcriptional level by extracellular signalling molecules, including epidermal growth factor (EGF), nerve growth factor (NGF) and glucocorticoids. We have analysed the stimulation of tyrosine hydroxylase gene transcription by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in noradrenergic locus coeruleus-like CATH.

Drosophila E2F1 has context-specific pro- and antiapoptotic properties during development.

E2F transcription factors are generally believed to be positive regulators of apoptosis. In this study, we show that dE2F1 and dDP are important for the normal pattern of DNA damage-induced apoptosis in Drosophila wing discs. Unexpectedly, the role that E2F plays varies depending on the position of the cells within the disc.