Biology subjects

Verdin, E.

Publications and source records attributed to Verdin, E..

4 recordsLinked to original sources

bioRxiv2018

Multi-Omic Profiling Reveals the Opposing Forces of Excess Dietary Sugar and Fat on Liver Mitochondria Protein Acetylation and Succinylation

Dietary macronutrient composition alters metabolism through several mechanisms, including post-translational modification (PTM) of proteins. To connect diet and molecular changes, here we performed short- and long-term feeding of mice with standard chow diet (SCD) and high-fat diet (HFD), with or without glucose or fructose supplementation, and quantified liver metabolites, 861 proteins, and 1,815 protein level-corrected mitochondrial acetylation and succinylation sites. Nearly half the acylation sites were altered by at least one diet; nutrient-specific changes in protein acylation sometimes encompass entire pathways. Although acetyl-CoA is an intermediate in both sugar and fat metabolism, acetyl-CoA had a dichotomous fate depending on its source; chronic feeding of dietary sugars induced protein hyperacetylation, whereas the same duration of HFD did not. Instead, HFD resulted in citrate accumulation, anaplerotic metabolism of amino acids, and protein hypo-succinylation. Together, our results demonstrate novel connections between dietary macronutrients, protein post-translational modifications, and regulation of fuel selection in liver.\n\nGraphical Abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC=\"FIGDIR/small/263426_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (53K):\norg.highwire.dtl.DTLVardef@1419c64org.highwire.dtl.DTLVardef@82a874org.highwire.dtl.DTLVardef@16023org.highwire.dtl.DTLVardef@4ed44e_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract\n\nC_FIG

systems biology↗

bioRxiv2018

Chromatin Functional States Correlate with HIV Latency Reversal in Infected Primary CD4+ T Cells

Human immunodeficiency virus (HIV) infection cannot be cured due to a small reservoir of latently infected CD4+ T cells in treated patients. The \"shock and kill\" approach proposes to eliminate the reservoir by inducing its activation and the direct or indirect killing of infected cells. Current latency reversing agents (LRAs) do not reduce the viral reservoir in treated patients.\n\nWe use a novel dual-fluorescent HIV reporter to identify and purify latent cells, and to determine the fraction of latent cells that undergo viral reactivation after infection of primary CD4+ T cells. Unexpectedly, LRAs reactivate less than 5% of latent proviruses. Analysis of HIV integration sites from induced and non-induced latent populations reveals distinct provirus integration sites between these two populations in terms of chromatin functional states.\n\nThese findings challenge \"shock and kill\", and suggest the need of more potent LRAs in combination with immunomodulatory approaches to eradicate HIV reservoir.

microbiology↗

bioRxiv2017

Histone Deacetylase 7 Mediates Tissue-Specific Autoimmunity via Control of Innate Effector Function in Invariant Natural Killer T-Cells

We report that Histone Deacetylase 7 (HDAC7) controls the thymic effector programming of Natural Killer T (NKT) cells, and that interference with this function contributes to tissue-specific autoimmunity. Gain of HDAC7 function in thymocytes blocks both negative selection and NKT development, diverting these cells into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes aberrant expansion of innate-effector cells. Investigating the mechanisms involved, we found that HDAC7 binds PLZF and modulates PLZF-dependent transcription. Moreover, HDAC7 and many of its transcriptional targets are human risk loci for IBD and PSC, autoimmune diseases that strikingly resemble the disease we observe in HDAC7 gain-of-function in mice. Importantly, reconstitution of iNKT cells in these mice abrogated their disease, suggesting that interaction between the defects in negative selection and iNKT cells caused by altered HDAC7 function can cause tissue-restricted autoimmunity, a finding that may explain the association between HDAC7 and hepatobiliary autoimmunity.

immunology↗

bioRxiv2017

Ketogenic diet or BHB improves epileptiform spikes, memory, survival in Alzheimer’s model

Links between epilepsy and Alzheimers disease (AD) are seen in both human patients and mouse models. Human patients with AD may commonly have subclinical epileptiform spikes (EP spikes)1, and overt epilepsy is associated with more rapid cognitive decline2. Mechanistic studies in mouse models of Alzheimers disease (AD) have shown that altered network activity and epileptiform spikes stem from dysfunctional inhibitory interneurons3, which are key elements of cortical circuits underlying cognition4. Treatments that reduce epileptiform spikes improve cognition in these models5,6. Thus, targeting subclinical epileptiform activity may be a promising new therapeutic approach to AD7. Ketogenic diet (KD) has long been used to treat forms of epilepsy8, including Dravet syndrome, a childhood epilepsy caused by mutations in a gene that is critical for inhibitory interneuron function in mouse AD models5,9. However, the concurrent effects of a ketogenic diet on brain electrical activity, cognitive decline, and survival have not been tested, and the translational rationale and feasibility of such an intervention remain uncertain. Here we show that a ketogenic diet reduces epileptiform spikes in the hAPPJ20 mouse model of AD. Similar reduction of EP spikes is observed using a {beta}-hydroxybutyrate (BHB) ester in both AD and Dravet mice. A ketogenic diet improves context-dependent and visuo-spatial learning in hAPPJ20 mice. It also reduces the high seizure-related mortality observed in male mice of this model. Therapies derived from {beta}-hydroxybutyrate may have potential application in ameliorating cognitive dysfunction in AD through reducing subclinical epileptiform activity.

neuroscience↗