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Diet-induced alteration of intestinal stem cell identity and lineage allocation underlies obesity and pre-diabetes in mice

ABSTRACT: Diet-induced alteration of intestinal stem cell identity and lineage allocation underlies obesity and pre-diabetes in mice

PROVIDER: PRJNA623558 | ENA |

REPOSITORIES: ENA

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Diet-induced alteration of intestinal stem cell identity and lineage allocation underlies obesity and pre-diabetes in mice

Project description:Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance causing obesity and increased risk for type 2 diabetes (T2D) and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). But, how an obesogenic diet affects ISC identity and fate decisions is not well understood. Here, we study the intestinal responses to an obesogenic diet in mice by combining single-cell profiling of more than 27,000 small intestinal crypt cells with genetic lineage labelling and tracing of ISC fate decisions and in situ metabolomics. We find that an obesogenic diet induces ISC and progenitor hyperproliferation, but also enhances ISC differentiation and cell turnover. Furthermore, the regional identity of ISCs and enterocytes is reprogrammed from a distal to a proximal phenotype and enterocyte zonation is altered to adapt cell function to nutrient availability. Single-cell resolution of the enteroendocrine lineage shows an increase in endocrine progenitors and peptidergic enteroendocrine cell (EEC) types and a decrease in serotonergic EEC types. Mechanistically, we can link increased fatty acid synthesis, Ppar signalling and the Insr/Igf1r/Akt pathway to ISC dysfunction, hyperproliferation and impaired endocrine differentiation. In summary, our work describes key molecular mechanisms of diet-induced intestinal maladaptation in mice that promote obesity, and, thus, underlie the pathogenesis of the metabolic syndrome and associated complications.

2021-07-15 | GSE148227 | GEO

Diet-induced alteration of intestinal stem cell function underlies obesity and pre-diabetes in mice

Project description:Diet-induced alteration of intestinal stem cell function underlies obesity and pre-diabetes in mice

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A non-canonical tricarboxylic acid cycle underlies cellular identity

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Chromatin plasticity contributes to neuronal selection during memory allocation

Project description:Memory allocation refers to the process by which neurons are recruited into the encoding ensemble to store learned information. This recruitment is regulated by neuronal selection based on differences in intrinsic excitability (IE) and the expression of the transcription factor CREB. However, whether other forms of plasticity influence memory allocation remains unknown. Here, we found that chromatin compaction and histone acetylation in the mouse lateral amygdala display a high degree of heterogeneity, a prerequisite for neuronal selection. Consequently, when we increased histone acetylation by overexpressing histone acetyl transferases (HATs), neurons with elevated histone acetylation were preferentially recruited into the encoding ensemble and memory retention was enhanced, while optogenetic silencing of the epigenetically altered neurons prevented memory expression. Mechanistically, using patch-clamp recordings and single-nucleus multi-ome sequencing, we observed that HAT overexpression increased IE and epitranscriptomic changes favoring synaptic plasticity. Lastly, by merging FRET-based epigenetic beacons with calcium indicators to simultaneously record histone acetylation and neuronal dynamics in real time, we found that epigenetic heterogeneity underlies IE in cell-autonomous manner. These results identify chromatin plasticity as a key factor catalyzing memory allocation.

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Proteome allocation constraints determine cellular growth rates and demand fitness trade-offs

Project description:Protein synthesis is costly and the proteome size is constrained. Using a genome-scale computational model of proteome allocation together with absolute proteomics data sets from many growth environments, we determine how these fundamental limitations constrain growth and fitness in Escherichia coli. First, we show that the observed variation in growth rates across environments is largely determined by the expression of protein not utilized for growth in a given environment. We then elucidate the overall transcriptional regulatory logic that underlies the expression of unused protein. We systematically classify the unused proteome into segments devoted to environmental readiness and stress resistance functions. While expression of these proteome segments incurs a fitness cost of decreased growth in a fixed environment, they provide fitness benefits in a changing environment. Thus, the systems biology of the prokaryotic proteome can be quantitatively understood based on resource allocation to growth, environmental readiness, and stress resistance functions.

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Diet-induced alteration of intestinal stem cell function underlies obesity and pre-diabetes in mice

Project description:This dataset consists of single-cell RNA-seq (10X) data from small intestinal crypts of healthy and HFHSD induced obese mice Foxa2-FVF/FVF mice and from small intestinal villi of healthy and HFHSD induced obese C57BL/6N mice. Mice were fed a HFHSD for 12 weeks. Intestinal crypt cell samples were FVF-enriched with FVF+ cells in a 1:1 ratio (50% FVF+, 50% FVF-) before sequencing.

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Dynamic regulation of chromatin accessibility and transcription factors underlies distinct organ identity and function

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Synovial fibroblast positional identity controlled by inductive Notch signaling underlies pathologic damage in inflammatory arthritis

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Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice.

Project description:Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr-Igf1r-Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications.

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Astrocyte allocation during brain development is controlled by Tcf4-mediated fate restriction

Project description:Astrocytes within specific brain regions contribute uniquely to regional circuits for higher-order brain function through interactions with local neurons. The regional diversification of astrocytes is dictated by their embryonic origin, yet the mechanisms governing their regional allocation remain unknown. Here we show that allocation of astrocytes to specific brain regions requires the transcription factor 4 (Tcf4) mediated fate restriction during brain development. Loss of Tcf4 in ventral telencephalic neural progenitors alters the fate of oligodendrocyte precursors to transient intermediate astrocyte precursor cells, resulting in mislocated astrocytes in the dorsal neocortex. These ectopic astrocytes originated from the ventral telencephalon engage with neurons and acquire features reminiscent of local neocortical astrocytes. Furthermore, Tcf4 functions as a suppressor of astrocyte fate during differentiation of oligodendrocyte precursors, thereby restricting the fate to oligodendrocyte lineage. Our study reveals that fate restriction governs regional astrocyte allocation, contributing to astrocyte diversification across brain regions.

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