scholarly journals Transcriptional integration of distinct microbial and nutritional signals by the small intestinal epithelium

2021 ◽  
Author(s):  
Colin R Lickwar ◽  
James M Davison ◽  
Cecelia Kelly ◽  
Gilberto Padilla Mercado ◽  
Jia Wen ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Energy Homeostasis ◽  
Rna Seq ◽  
High Fat ◽  
Adult Mice ◽  
Proliferation And Differentiation ◽  
Microbial Responses ◽  
Intestinal Proliferation ◽  
Small Intestinal ◽  
Simultaneous Influence

To preserve its physiologic functions, the intestine must interpret and adapt to complex combinations of stimuli from dietary and microbial sources. However, the transcriptional strategies by which the intestinal epithelium integrates and adapts to dietary and microbial information remains unresolved. We compared adult mice reared germ free (GF) or conventionalized with a microbiota (CV) either fed normally or after a single high-fat meal (HFM). Jejunal epithelium preparations were queried using genomewide assays for RNA-seq, the activating histone mark H3K27ac ChIP-seq, and ChIP-seq of the microbially-responsive transcription factor HNF4A. We identified distinct nutritional and microbial responses at certain genes, but also apparent simultaneous influence of both stimuli at many other loci and regulatory regions. Increased expression levels and H3K27ac enrichment following HFM at a subset of these sites was dependent on microbial status. H3K27ac sites that were preferentially increased by HFM in the presence of microbes neighbor lipid anabolism and proliferation genes as well as intestinal stem cell (ISC) markers, were usually active only in ISCs, and were not HNF4A targets. In contrast, H3K27ac sites that were preferentially increased by HFM in the absence of microbes neighbored targets of the nuclear receptor and energy homeostasis regulator PPARA, were frequently accessible only in enterocytes, and were HNF4A bound. These results reveal that HNF4A supports a differentiated enterocyte and FAO program in GF, and that suppression of HNF4A by the combination of microbes and HFM may result in preferential activation of IEC proliferation programs. Microbial and nutritional responses are therefore integrated with some of the same transcriptional programs that regulate intestinal proliferation and differentiation.

scholarly journals Cannabinoid CB1 Receptors in the Intestinal Epithelium Are Required for Acute Western-Diet Preferences in Mice

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2874
Author(s):  
Bryant Avalos ◽  
Donovan A. Argueta ◽  
Pedro A. Perez ◽  
Mark Wiley ◽  
Courtney Wood ◽  
...  
Keyword(s):  
Intestinal Epithelium ◽  
Endocannabinoid System ◽  
Dietary Fats ◽  
Treatment Preferences ◽  
Palatable Food ◽  
High Fat ◽  
Small Intestinal Epithelium ◽  
Diet Induced Obesity ◽  
Small Intestinal ◽  
Deficient Mice

The endocannabinoid system plays an important role in the intake of palatable food. For example, endocannabinoid signaling in the upper small-intestinal epithelium is increased (i) in rats after tasting dietary fats, which promotes intake of fats, and (ii) in a mouse model of diet-induced obesity, which promotes overeating via impaired nutrient-induced gut–brain satiation signaling. We now utilized a combination of genetic, pharmacological, and behavioral approaches to identify roles for cannabinoid CB1Rs in upper small-intestinal epithelium in preferences for a western-style diet (WD, high-fat/sucrose) versus a standard rodent diet (SD, low-fat/no sucrose). Mice were maintained on SD in automated feeding chambers. During testing, mice were given simultaneous access to SD and WD, and intakes were recorded. Mice displayed large preferences for the WD, which were inhibited by systemic pretreatment with the cannabinoid CB1R antagonist/inverse agonist, AM251, for up to 3 h. We next used our novel intestinal epithelium-specific conditional cannabinoid CB1R-deficient mice (IntCB1−/−) to investigate if intestinal CB1Rs are necessary for WD preferences. Similar to AM251 treatment, preferences for WD were largely absent in IntCB1−/− mice when compared to control mice for up to 6 h. Together, these data suggest that CB1Rs in the murine intestinal epithelium are required for acute WD preferences.

scholarly journals The HSP90/R2TP assembly chaperone promotes cell proliferation in the intestinal epithelium

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chloé Maurizy ◽  
Claire Abeza ◽  
Bénédicte Lemmers ◽  
Monica Gabola ◽  
Ciro Longobardi ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Intestinal Epithelium ◽  
Core Component ◽  
Proliferating Cells ◽  
Knock Out ◽  
Differentiated Cells ◽  
Adult Mice ◽  
Cycle Arrest ◽  
Small Intestinal ◽  
Knock Out Mice

AbstractThe R2TP chaperone cooperates with HSP90 to integrate newly synthesized proteins into multi-subunit complexes, yet its role in tissue homeostasis is unknown. Here, we generated conditional, inducible knock-out mice for Rpap3 to inactivate this core component of R2TP in the intestinal epithelium. In adult mice, Rpap3 invalidation caused destruction of the small intestinal epithelium and death within 10 days. Levels of R2TP substrates decreased, with strong effects on mTOR, ATM and ATR. Proliferative stem cells and progenitors deficient for Rpap3 failed to import RNA polymerase II into the nucleus and they induced p53, cell cycle arrest and apoptosis. Post-mitotic, differentiated cells did not display these alterations, suggesting that R2TP clients are preferentially built in actively proliferating cells. In addition, high RPAP3 levels in colorectal tumors from patients correlate with bad prognosis. Here, we show that, in the intestine, the R2TP chaperone plays essential roles in normal and tumoral proliferation.

Effects of dietary n-3 PUFA levels in early life on susceptibility to high-fat-diet-induced metabolic syndrome in adult mice

2020 ◽  
pp. 108578
Author(s):  
Dan-Dan Wang ◽  
Fang Wu ◽  
Ling-Yu Zhang ◽  
Ying-Cai Zhao ◽  
Cheng-Cheng Wang ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
High Fat Diet ◽  
Early Life ◽  
High Fat ◽  
Adult Mice

scholarly journals MicroRNA-27b-3p Targets the Myostatin Gene to Regulate Myoblast Proliferation and Is Involved in Myoblast Differentiation

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 423
Author(s):  
Genxi Zhang ◽  
Mingliang He ◽  
Pengfei Wu ◽  
Xinchao Zhang ◽  
Kaizhi Zhou ◽  
...  
Keyword(s):  
Muscle Growth ◽  
Luciferase Reporter ◽  
Myoblast Differentiation ◽  
Regulation Mechanism ◽  
Rna Seq ◽  
Myostatin Gene ◽  
Primary Myoblasts ◽  
Chicken Muscle ◽  
Proliferation And Differentiation ◽  
Myoblast Proliferation

microRNAs play an important role in the growth and development of chicken embryos, including the regulation of skeletal muscle genesis, myoblast proliferation, differentiation, and apoptosis. Our previous RNA-seq studies showed that microRNA-27b-3p (miR-27b-3p) might play an important role in regulating the proliferation and differentiation of chicken primary myoblasts (CPMs). However, the mechanism of miR-27b-3p regulating the proliferation and differentiation of CPMs is still unclear. In this study, the results showed that miR-27b-3p significantly promoted the proliferation of CPMs and inhibited the differentiation of CPMs. Then, myostatin (MSTN) was confirmed to be the target gene of miR-27b-3p by double luciferase reporter assay, RT-qPCR, and Western blot. By overexpressing and interfering with MSTN expression in CPMs, the results showed that overexpression of MSTN significantly inhibited the proliferation and differentiation of CPMs. In contrast, interference of MSTN expression had the opposite effect. This study showed that miR-27b-3p could promote the proliferation of CPMs by targeting MSTN. Interestingly, both miR-27b-3p and MSTN can inhibit the differentiation of CPMs. These results provide a theoretical basis for further understanding the function of miR-27b-3p in chicken and revealing its regulation mechanism on chicken muscle growth.

scholarly journals Distinct Changes in Gut Microbiota Are Associated with Estradiol-Mediated Protection from Diet-Induced Obesity in Female Mice

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 499
Author(s):  
Kalpana D. Acharya ◽  
Hye L. Noh ◽  
Madeline E. Graham ◽  
Sujin Suk ◽  
Randall H. Friedline ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Energy Homeostasis ◽  
Whole Body ◽  
Glucose Turnover ◽  
Female Mice ◽  
Adult Mice ◽  
Diet Induced Obesity ◽  
Metabolic Dysregulation ◽  
Regulation Of Metabolism ◽  
Junction Protein

A decrease in ovarian estrogens in postmenopausal women increases the risk of weight gain, cardiovascular disease, type 2 diabetes, and chronic inflammation. While it is known that gut microbiota regulates energy homeostasis, it is unclear if gut microbiota is associated with estradiol regulation of metabolism. In this study, we tested if estradiol-mediated protection from high-fat diet (HFD)-induced obesity and metabolic changes are associated with longitudinal alterations in gut microbiota in female mice. Ovariectomized adult mice with vehicle or estradiol (E2) implants were fed chow for two weeks and HFD for four weeks. As reported previously, E2 increased energy expenditure, physical activity, insulin sensitivity, and whole-body glucose turnover. Interestingly, E2 decreased the tight junction protein occludin, suggesting E2 affects gut epithelial integrity. Moreover, E2 increased Akkermansia and decreased Erysipleotrichaceae and Streptococcaceae. Furthermore, Coprobacillus and Lactococcus were positively correlated, while Akkermansia was negatively correlated, with body weight and fat mass. These results suggest that changes in gut epithelial barrier and specific gut microbiota contribute to E2-mediated protection against diet-induced obesity and metabolic dysregulation. These findings provide support for the gut microbiota as a therapeutic target for treating estrogen-dependent metabolic disorders in women.

scholarly journals Single-nucleus RNA-seq and FISH identify coordinated transcriptional activity in mammalian myofibers

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Matthieu Dos Santos ◽  
Stéphanie Backer ◽  
Benjamin Saintpierre ◽  
Brigitte Izac ◽  
Muriel Andrieu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Transcription Factors ◽  
Neuromuscular Junction ◽  
Heavy Chain ◽  
Transcriptional Activity ◽  
Rna Seq ◽  
Hybrid Fibers ◽  
Adult Mice ◽  
Single Nucleus

Abstract Skeletal muscle fibers are large syncytia but it is currently unknown whether gene expression is coordinately regulated in their numerous nuclei. Here we show by snRNA-seq and snATAC-seq that slow, fast, myotendinous and neuromuscular junction myonuclei each have different transcriptional programs, associated with distinct chromatin states and combinations of transcription factors. In adult mice, identified myofiber types predominantly express either a slow or one of the three fast isoforms of Myosin heavy chain (MYH) proteins, while a small number of hybrid fibers can express more than one MYH. By snRNA-seq and FISH, we show that the majority of myonuclei within a myofiber are synchronized, coordinately expressing only one fast Myh isoform with a preferential panel of muscle-specific genes. Importantly, this coordination of expression occurs early during post-natal development and depends on innervation. These findings highlight a previously undefined mechanism of coordination of gene expression in a syncytium.

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