Several autoimmune diseases including multiple sclerosis (MS) cause increased transcription of endogenous retroviruses (HERVs) normally repressed by heterochromatin. In parallel, HERV-derived ...sequences were reported to drive gene expression. Here, we have examined a possible link between promoter and enhancer divergent transcription and the production of HERV transcripts. We find that HERV-derived sequences are in general counter-selected at regulatory regions, a counter-selection that is strongest in brain tissues while very moderate in stem cells. By exposing T cells to the pesticide dieldrin, we further found that a series of HERV-driven enhancers otherwise active only at stem cell stages can be reactivated by stress. This in part relies on peptidylarginine deiminase activity, possibly participating in the reawakening of silenced enhancers. Likewise, usage of HERV-driven enhancers was increased in myelin-reactive T cells from patients with MS, correlating with activation of nearby genes at several sites. Altogether, we propose that HERV-driven enhancers constitute a reservoir of auxiliary enhancers transiently induced by stress while chronically active in diseases like MS.
Heterochromatin protein 1 (HP1) proteins are chromatin‐bound transcriptional regulators. While their chromodomain binds histone H3 methylated on lysine 9, their chromoshadow domain associates with ...the H3 histone fold in a region involved in chromatin remodeling. Here, we show that phosphorylation at histone H3 threonine 45 and serine 57 within this latter region differentially affects binding of the three mammalian HP1 isoforms HP1α, HP1β and HP1γ. Both phosphorylation events are dependent on the activity of the DYRK1A kinase that antagonizes HP1‐mediated transcriptional repression and participates in abnormal activation of cytokine genes in Down's syndrome‐associated megakaryoblastic leukemia.
Synopsis
DYRK1A counteracts chromatin‐mediated transcriptional repression of pro‐inflammatory genes by phosphorylating histone H3 at the genes' promoters. Inhibiting excessive DYRK1A activity in megakaryoblastic leukemia linked to Down's syndrome might be a way to control the pro‐inflammatory cytokinemia associated with this disease.
Binding of HP1α, HP1β, and HP1γ to the globular domain of histone H3 is differentially regulated by phosphorylation of residues H3T45 and H3S57.
At pro‐inflammatory gene promoters, the Down's syndrome‐associated DYRK1A kinase phosphorylates these histone H3 residues and interferes with HP1‐mediated transcriptional repression.
Inhibition of DYRK1A activity in megakaryoblastic leukemia cells from Down's syndrome patients decreases the expression of pro‐inflammatory genes.
DYRK1A counteracts chromatin‐mediated transcriptional repression of pro‐inflammatory genes by phosphorylating histone H3 at the genes' promoters. Inhibiting excessive DYRK1A activity in megakaryoblastic leukemia linked to Down's syndrome might be a way to control the pro‐inflammatory cytokinemia associated with this disease.
Multiple Sclerosis (MS) is an autoimmune disease associated with abnormal expression of a subset of cytokines, resulting in inappropriate T-lymphocyte activation and uncontrolled immune response. A ...key issue in the field is the need to understand why these cytokines are transcriptionally activated in the patients. Here, we have examined several transcription units subject to pathological reactivation in MS, including the TNFα and IL8 cytokine genes and also several Human Endogenous RetroViruses (HERVs). We find that both the immune genes and the HERVs require the heterochromatin protein HP1α for their transcriptional repression. We further show that the Peptidylarginine Deiminase 4 (PADI4), an enzyme with a suspected role in MS, weakens the binding of HP1α to tri-methylated histone H3 lysine 9 by citrullinating histone H3 arginine 8. The resulting de-repression of both cytokines and HERVs can be reversed with the PADI-inhibitor Cl-amidine. Finally, we show that in peripheral blood mononuclear cells (PBMCs) from MS patients, the promoters of TNFα, and several HERVs share a deficit in HP1α recruitment and an augmented accumulation of histone H3 with a double citrulline 8 tri-methyl lysine 9 modifications. Thus, our study provides compelling evidence that HP1α and PADI4 are regulators of both immune genes and HERVs, and that multiple events of transcriptional reactivation in MS patients can be explained by the deficiency of a single mechanism of gene silencing.
The heterochromatin-enriched HP1 proteins play a critical role in regulation of transcription. These proteins contain two related domains known as the chromo- and the chromoshadow-domain. The ...chromo-domain binds histone H3 tails methylated on lysine 9. However, in vivo and in vitro experiments have shown that the affinity of HP1 proteins to native methylated chromatin is relatively poor and that the opening of chromatin occurring during DNA replication facilitates their binding to nucleosomes. These observations prompted us to investigate whether HP1 proteins have additional histone binding activities, envisioning also affinity for regions potentially occluded by the nucleosome structure. We find that the chromoshadow-domain interacts with histone H3 in a region located partially inside the nucleosomal barrel at the entry/exit point of the nucleosome. Interestingly, this region is also contacted by the catalytic subunits of the human SWI/SNF complex. In vitro, efficient SWI/SNF remodeling requires this contact and is inhibited in the presence of HP1 proteins. The antagonism between SWI/SNF and HP1 proteins is also observed in vivo on a series of interferon-regulated genes. Finally, we show that SWI/SNF activity favors loading of HP1 proteins to chromatin both in vivo and in vitro. Altogether, our data suggest that HP1 chromoshadow-domains can benefit from the opening of nucleosomal structures to bind chromatin and that HP1 proteins use this property to detect and arrest unwanted chromatin remodeling.
Several autoimmune diseases including multiple sclerosis (MS) cause increased transcription of endogenous retroviruses (HERVs) normally repressed by heterochromatin. In parallel, HERV‐derived ...sequences were reported to drive gene expression. Here, we have examined a possible link between promoter and enhancer divergent transcription and the production of HERV transcripts. We find that HERV‐derived sequences are in general counter‐selected at regulatory regions, a counter‐selection that is strongest in brain tissues while very moderate in stem cells. By exposing T cells to the pesticide dieldrin, we further found that a series of HERV‐driven enhancers otherwise active only at stem cell stages can be reactivated by stress. This in part relies on peptidylarginine deiminase activity, possibly participating in the reawakening of silenced enhancers. Likewise, usage of HERV‐driven enhancers was increased in myelin‐reactive T cells from patients with MS, correlating with activation of nearby genes at several sites. Altogether, we propose that HERV‐driven enhancers constitute a reservoir of auxiliary enhancers transiently induced by stress while chronically active in diseases like MS.
Synopsis
Human endogenous retroviruses (HERVs) derived from ancient exogenous viruses can act as cis‐enhancers. This study shows that increased disease‐related gene expression is in part due to a chronic increase of HERV cis‐enhancer activity in the context of autoimmune diseases.
Enhancers driven by HERVs are enriched in the neighborhood of immune genes.
HERV‐driven enhancers are mostly active in embryonic cells but silenced in mature adult tissues.
Extensive stress causes transient reactivation of HERV transcription.
In multiple sclerosis, some HERV‐driven regulatory regions become chronically active.
Stress‐responsive cis‐enhancer activity of human endogenous retroviruses is chronically induced in the context of autoimmune diseases.
ABMA and its analogue DABMA are two molecules of the adamantane family known to perturbate the endosomal pathway and to inhibit cell infection of several RNA and DNA viruses. Their activity against ...Rabies Virus (RABV) infection has already been demonstrated in vitro. (Wu et al., 2017, 2019). Here, we describe in more details their mechanism of action by comparison to Arbidol (umifenovir) and Ribavirin, two broad spectrum antivirals against emerging viruses such as Lassa, Ebola, influenza and Hantaan viruses. ABMA and DABMA, delivered 2 h pre-infection, inhibit RABV infection in vitro with an EC50 of 7.8 μM and 14 μM, respectively. They act at post-entry, by causing RABV accumulation within the endosomal compartment and DABMA specifically diminishes the expression of the GTPase Rab7a controlling the fusion of early endosomes to late endosomes or lysosomes. This may suggest that ABMA and DABMA act at different stages of the late endosomal pathway as supported by their different profile of synergy/antagonism with the fusion inhibitor Arbidol. This difference is further confirmed by the RABV mutants induced by successive passages under increasing selective pressure showing a particular involvement of the viral G protein in the DABMA inhibition while ABMA inhibition induces less mutations dispersed in the M, G and L viral proteins. These results suggest new therapeutic perspectives against rabies.
•ABMA and DABMA, adamantane like compounds, are two compounds designed to block the retrograde transport of Ricin.•The mechanism of action of ABMA and DABMA on Rabies Virus in vitro by comparison with Arbidol (umefenovir) and Ribavirin.•The effect of ABMA and DABMA on endosomal pathway is described.•Synergies of ABMA, DABMA and ARBIDOL on Rabies Virus infection in vitro are described.•Rabies virus mutants were generated under the pressure of ABMA and DABMA.
Evolution of H5N1 avian influenza viruses in Asia World Health Organization Global Influenza Program Surveillance Network, /; Aubin, Jean-Thierry; Azebi, Saliha ...
Emerging infectious diseases,
10/2005, Volume:
11, Issue:
10
Journal Article
Peer reviewed
Open access
An outbreak of highly pathogenic avian influenza A (H5N1) has recently spread to poultry in 9 Asian countries. H5N1 infections have caused > or =52 human deaths in Vietnam, Thailand, and Cambodia ...from January 2004 to April 2005. Genomic analyses of H5N1 isolates from birds and humans showed 2 distinct clades with a nonoverlapping geographic distribution. All the viral genes were of avian influenza origin, which indicates absence of reassortment with human influenza viruses. All human H5N1 isolates tested belonged to a single clade and were resistant to the adamantane drugs but sensitive to neuraminidase inhibitors. Most H5N1 isolates from humans were antigenically homogeneous and distinct from avian viruses circulating before the end of 2003. Some 2005 isolates showed evidence of antigenic drift. An updated nonpathogenic H5N1 reference virus, lacking the polybasic cleavage site in the hemagglutinin gene, was produced by reverse genetics in anticipation of the possible need to vaccinate humans.
La sclérose en plaques est une maladie auto-immune dirigée contre les protéines de la myéline du cerveau. Plusieurs mécanismes physiopathologiques sont impliqués dans la SEP tels que l'inflammation, ...la démyélinisation et l’atteinte axonale. La SEP est associée à une expression accrue de cytokines et à une activation des rétrovirus endogènes humains (HERVs). Dans les conditions physiologiques, ces unités transcriptionnelles sont maintenues dans un état réprimé par un même mécanisme répresseur dépendant de la chromatine : la tri-méthylation de la lysine 9 de l’histone H3 (H3K9me3), qui crée un site de liaison aux protéines de la famille HP1. Nous avons trouvé qu’à la fois, les gènes de l’immunité et les HERVs nécessitent les protéines hétérochromatiniennes HP1α pour leur répression transcriptionnelle. Nous avons montré que la peptidylarginine déiminase 4, une enzyme qui joue un rôle dans la SEP, affaiblit la liaison de HP1α à la lysine 9 tri-méthylée de l'histone H3 en citrullinant l’arginine 8. Nous avons apporté la preuve que de multiples événements de la réactivation de la transcription chez les patients atteints de la SEP peuvent être expliqués par un défaut du mécanisme unique de répression génique. Nous avons également montré qu'il est possible de renforcer la répression de HP1 à l'aide de petites molécules. Par exemple, l’EGCG, un composé de thé vert, est en mesure de réduire à la fois l’expression des HERVs et des cytokines en augmentant l'activité de l’histone méthyltransférase SUV39H1. Cela conduit à une accumulation de la marque répressive H3K9me3, qui va favoriser la liaison de HP1.Ensemble, ces résultats suggèrent que HP1 est une composante importante de la SEP au niveau de la régulation des cytokines et des HERVs.
Multiple Sclerosis is an autoimmune disease resulting in damage to myelin structures of the brain. Several physiopathological mechanisms are involved in MS including inflammation, demyelination, and axonal damage. MS is associated with increased cytokine expression and activation of human endogenous retroviruses (HERVs). These two types of transcriptional units are kept in check by chromatin-dependent silencing associated with lysine 9 trimethylation of histone H3, and subsequent of HP1 proteins. We find that both the cytokine genes and the HERVs require the heterochromatin protein HP1 for their transcriptional repression. Furthermore, we have shown that the peptidylarginine deiminase 4, an enzyme with a suspected role in MS, weakens the binding of HP1 to tri-methylated histone H3 lysine 9 by citrullinating histone H3 arginine 8. We thereby evidence that multiple events of transcriptional reactivation in MS patients can be explained by deficiency of a single mechanism of gene silencing. We have also shown that it is possible to reinforce HP1 repression by using small molecules. For example, EGCG, a green tea compound, is able to reduce both HERVs and cytokines expression by increasing histone methyltransferase activity SUV39H1. This leads to increased accumulation of H3K9me3 repressive marks and favors binding of HP1. All together, these results suggest that HP1 is an important component of the regulation of cytokine genes and HERVs in MS patients.
The heterochromatin-enriched HP1 proteins play a critical role in regulation of transcription. These proteins contain two related domains known as the chromo-and the chromoshadow-domain. The ...chromo-domain binds histone H3 tails methylated on lysine 9. However, in vivo and in vitro experiments have shown that the affinity of HP1 proteins to native methylated chromatin is relatively poor and that the opening of chromatin occurring during DNA replication facilitates their binding to nucleosomes. These observations prompted us to investigate whether HP1 proteins have additional histone binding activities, envisioning also affinity for regions potentially occluded by the nucleosome structure. We find that the chromoshadow-domain interacts with histone H3 in a region located partially inside the nucleosomal barrel at the entry/exit point of the nucleosome. Interestingly, this region is also contacted by the catalytic subunits of the human SWI/SNF complex. In vitro, efficient SWI/SNF remodeling requires this contact and is inhibited in the presence of HP1 proteins. The antagonism between SWI/SNF and HP1 proteins is also observed in vivo on a series of interferon-regulated genes. Finally, we show that SWI/SNF activity favors loading of HP1 proteins to chromatin both in vivo and in vitro. Altogether, our data suggest that HP1 chromoshadow-domains can benefit from the opening of nucleosomal structures to bind chromatin and that HP1 proteins use this property to detect and arrest unwanted chromatin remodeling. Citation: Lavigne M, Eskeland R, Azebi S, Saint-André V, Jang SM, et al. (2009) Interaction of HP1 and Brg1/Brm with the Globular Domain of Histone H3 Is Required for HP1-Mediated Repression. PLoS Genet 5(12): e1000769.
The heterochromatin-enriched HP1 proteins play a critical role in regulation of transcription. These proteins contain two related domains known as the chromo- and the chromoshadow-domain. The ...chromo-domain binds histone H3 tails methylated on lysine 9. However, in vivo and in vitro experiments have shown that the affinity of HP1 proteins to native methylated chromatin is relatively poor and that the opening of chromatin occurring during DNA replication facilitates their binding to nucleosomes. These observations prompted us to investigate whether HP1 proteins have additional histone binding activities, envisioning also affinity for regions potentially occluded by the nucleosome structure. We find that the chromoshadow-domain interacts with histone H3 in a region located partially inside the nucleosomal barrel at the entry/exit point of the nucleosome. Interestingly, this region is also contacted by the catalytic subunits of the human SWI/SNF complex. In vitro, efficient SWI/SNF remodeling requires this contact and is inhibited in the presence of HP1 proteins. The antagonism between SWI/SNF and HP1 proteins is also observed in vivo on a series of interferon-regulated genes. Finally, we show that SWI/SNF activity favors loading of HP1 proteins to chromatin both in vivo and in vitro. Altogether, our data suggest that HP1 chromoshadow-domains can benefit from the opening of nucleosomal structures to bind chromatin and that HP1 proteins use this property to detect and arrest unwanted chromatin remodeling.
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