Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity

Dávalos-Salas, Mercedes; Montgomery, Magdalene K; Reehorst, Camilla M; Nightingale, Rebecca; Ng, Irvin; Anderton, Holly; Al-Obaidi, Sheren; Lesmana, Analia; Scott, Cameron M.; Ioannidis, Paul; Kalra, Hina; Keerthikumar, Shivakumar; Tögel, Lars; Rigopoulos, Angela; Gong, Sylvia; Williams, David S.; Yoganantharaja, Prusoth; Bell-Anderson, Kim; Mathivanan, Suresh; Gibert, Yann; Hiebert, Scott W.; Scott, Andrew; Watt, Matthew J.; Mariadason, John M.

doi:10.1038/s41467-019-13180-8

Cited by 47 publications

(23 citation statements)

References 55 publications

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“…Hence, bacterial signals at barrier surfaces are integrated through multiple regulatory layers convergent in NFIL3 and circadian function. Notably, epithelial NFIL3 controls expression of a circadian lipid metabolic program which is also regulated by the histone deacetylase HDAC3 (Alenghat et al, 2013;Wang et al, 2017;Dávalos-Salas et al, 2019). Along these lines, intestinal HDAC3 expression is induced by gut microbes and is rhythmically recruited to chromatin together with the corepressor NCoR and the clock protein Rev-Erbα, directly imposing diurnal rhythms in H3K9ac and H3K27ac at the regulatory regions of genes involved in lipid metabolism and nutrient transport (Kuang et al, 2019) (Figure 2).…”

Section: Nfil3 and Hdac3 Relay Inputs From Intestinal Microbes To Thementioning

confidence: 99%

Circadian Regulation of Immunity Through Epigenetic Mechanisms

Orozco-Solís

Aguilar-Arnal

2020

Front. Cell. Infect. Microbiol.

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The circadian clock orchestrates daily rhythms in many physiological, behavioral and molecular processes, providing means to anticipate, and adapt to environmental changes. A specific role of the circadian clock is to coordinate functions of the immune system both at steady-state and in response to infectious threats. Hence, time-of-day dependent variables are found in the physiology of immune cells, host-parasite interactions, inflammatory processes, or adaptive immune responses. Interestingly, the molecular clock coordinates transcriptional-translational feedback loops which orchestrate daily oscillations in expression of many genes involved in cellular functions. This clock function is assisted by tightly controlled transitions in the chromatin fiber involving epigenetic mechanisms which determine how a when transcriptional oscillations occur. Immune cells are no exception, as they also present a functional clock dictating transcriptional rhythms. Hereby, the molecular clock and the chromatin regulators controlling rhythmicity represent a unique scaffold mediating the crosstalk between the circadian and the immune systems. Certain epigenetic regulators are shared between both systems and uncovering them and characterizing their dynamics can provide clues to design effective chronotherapeutic strategies for modulation of the immune system.

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Section: Nfil3 and Hdac3 Relay Inputs From Intestinal Microbes To Thementioning

confidence: 99%

Circadian Regulation of Immunity Through Epigenetic Mechanisms

Orozco-Solís

Aguilar-Arnal

2020

Front. Cell. Infect. Microbiol.

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“…Indeed, miRNAs participate in processes of intestinal epithelial differentiation ( Dalmasso et al, 2010 ) and barrier function ( Ye et al, 2011 ). Moreover, miRNAs modulate the expression of certain lipids, cholesterol, and FA synthesis and metabolism-related genes ( Gil-Zamorano et al, 2014 ), like 3- Hydroxy-3-methylglutaryl coenzyme A synthase (Hmgcs) , Acetyl-CoA acetyltransferase (Acat) , fatty acid synthase (Fasn) , ATP-Binding Cassette Transporter A (Abca) , C-Protein reactive (Crp) or Scavenger receptor class B type 1 ( Briand et al, 2016 ; Davalos-Salas et al, 2019 ). Yet, it is likely that many other miRNA-regulated genes involved in intestinal lipid metabolism remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Intestinal Lipid Metabolism Genes Regulated by miRNAs

Ruiz-Roso¹,

Gil-Zamorano²,

Hazas³

et al. 2020

Front. Genet.

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MicroRNAs (miRNAs) crucial roles in translation repression and post-transcriptional adjustments contribute to regulate intestinal lipid metabolism. Even though their actions in different metabolic tissues have been elucidated, their intestinal activity is yet unclear. We aimed to investigate intestinal miRNA-regulated lipid metabolism-related genes, by creating an intestinal-specific Dicer1 knockout (Int-Dicer1 KO) mouse model, with a depletion of microRNAs in enterocytes. The levels of 83 cholesterol and lipoprotein metabolism-related genes were assessed in the intestinal mucosa of Int-Dicer1 KO and Wild Type C57BL/6 (WT) littermates mice at baseline and 2 h after an oral lipid challenge. Among the 18 genes selected for further validation, Hmgcs2, Acat1 and Olr1 were found to be strong candidates to be modulated by miRNAs in enterocytes and intestinal organoids. Moreover, we report that intestinal miRNAs contribute to the regulation of intestinal epithelial differentiation. Twenty-nine common miRNAs found in the intestines were analyzed for their potential to target any of the three candidate genes found and validated by miRNA-transfection assays in Caco-2 cells. MiR-31-5p, miR-99b-5p, miR-200a-5p, miR-200b-5p and miR-425-5p are major regulators of these lipid metabolism-related genes. Our data provide new evidence on the potential of intestinal miRNAs as therapeutic targets in lipid metabolism-associated pathologies.

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“…HDACs have been defined as a group of enzymes that play significant roles in mediating multiple processes at cellular and molecular levels (Merarchi et al, 2019). One of its members, Hdac3, has been reported to manage the gene expression in various tissues related to lipid metabolism (Davalos-Salas et al, 2019). In a mouse model of DM, the inhibition of Hdac3 has been reported to activate NF-E2-related factor 2 to alleviate liver damage caused by DM (Zhang et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase 3 Aggravates Type 1 Diabetes Mellitus by Inhibiting Lymphocyte Apoptosis Through the microRNA-296-5p/Bcl-xl Axis

Che

Yang

et al. 2020

Front. Genet.

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Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by immune-mediated destruction of pancreatic beta-cells. Multiple microRNAs (miRNAs) have been implicated in T1DM pathogenesis. Although histone deacetylase 3 (HDAC3) has been reported to be involved in T1DM, the underlying mechanisms remain to be further elucidated. This study was designed to investigate the potential regulatory role of Hdac3 on T1DM progression. The expression of miR-296-5p and B-cell leukemia-XL (BCL-XL) was determined using RT-qPCR and Western blot assay in peripheral blood mononuclear cells (PBMCs) of patients with T1DM, tumor necrosis factor-α (TNF-α)-and cycloheximide (CHX)-induced cell model, and streptozotocin (STZ)-induced rat model. The binding affinity between miR-296-5p and Bcl-xl was verified by using dual-luciferase reporter gene assay, and the binding between Hdac3 and the promoter region of miR-296-5p was validated using chromatin immunoprecipitation assay. Western blot analysis and flow cytometry were conducted to assess the apoptotic events of lymphocytes. miR-296-5p expression was downregulated while BCL-XL expression was upregulated in PBMCs of patients with T1DM. An adverse correlation was identified between miR-296-5p and Bcl-xl in mouse TE15 B lymphocytes. Bcl-xl was further validated to be targeted and negatively regulated by miR-296-5p in 293 T cells. Hdac3 inhibited miR-296-5p expression by binding to its promoter region. The effects of overexpressed Hdac3 on lymphocyte apoptosis was counterweighed via downregulation of Bcl-xl or upregulation of miR-296-5p, the mechanism of which was further validated in a rat model of DM. Taken together, the Hdac3-mediated upregulation of Bcl-xl via inhibiting miR-296-5p promoter activity enhanced the antiapoptotic capacity of lymphocytes to accelerate the occurrence of T1DM.

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Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity

Cited by 47 publications

References 55 publications

Circadian Regulation of Immunity Through Epigenetic Mechanisms

Circadian Regulation of Immunity Through Epigenetic Mechanisms

Intestinal Lipid Metabolism Genes Regulated by miRNAs

Histone Deacetylase 3 Aggravates Type 1 Diabetes Mellitus by Inhibiting Lymphocyte Apoptosis Through the microRNA-296-5p/Bcl-xl Axis

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