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Tnfaip2/Exoc3 controls exit from pluripotency by mediating lipid droplet formation and FA-induced differentiation

ABSTRACT: The decline in stem cell function leads to impairments in tissue homeostasis but genetic factors that control differentiation and de-differentiation of stem cells in the context of tissue homeostasis remain to be delineated. Here we show that Tnfaip2 (a target gene of TNFa/NFkB signaling) has an essential role for the differentiation of pluripotent, embryonic stem cells (ESCs). Knockdown of the planarian pseudo-orthologue, Smed-exoc3, impairs pluripotent stem cell differentiation, tissue homeostasis and regeneration in vivo. The study shows that Tnfaip2 deletion impairs changes in lipid metabolism that drive differentiation induction of ESCs. The application of palmitic acid (PA, the most abundant saturated fatty acid in mammalian cells) and palmitoylcarnitine (a mitochondrial carrier of PA) fully restores the differentiation of ESCs as well as the differentiation of pluripotent stem cells and organ maintenance in Smed-exoc3-depleted planarians. Together, these results identify a novel pathway downstream of TNFa/NFkB signaling, which is essential for exit from pluripotency by mediating changes in lipid metabolism.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Suspension Culture, Embryonic Stem Cell

SUBMITTER: Alessandro Ori

LAB HEAD: K. Lenhard Rudolph

PROVIDER: PXD014628 | Pride | 2020-11-18

REPOSITORIES: Pride

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			Action	DRS
	171122_JMK_SD_DIA_0_KO_1.raw	Raw
	171122_JMK_SD_DIA_0_KO_2.raw	Raw
	171122_JMK_SD_DIA_0_KO_3.raw	Raw
	171122_JMK_SD_DIA_0_KO_4.raw	Raw
	171122_JMK_SD_DIA_0_KO_5.raw	Raw

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Project description:Genome-wide mapping of transcriptional regulatory elements are essential tools for the understanding of the molecular events orchestrating self-renewal, commitment and differentiation of stem cells. We combined high-throughput identification of nascent, Pol-II-transcribed RNAs by Cap Analysis of Gene Expression (CAGE-Seq) with genome-wide profiling of histones modifications by chromatin immunoprecipitation (ChIP-seq) to map active promoters and enhancers in a model of human neural commitment, represented by embryonic stem cells (ESCs) induced to differentiate into self-renewing neuroepithelial-like stem cells (NESC). We integrated CAGE-seq, ChIP-seq and gene expression profiles to discover shared or cell-specific regulatory elements, transcription start sites and transcripts associated to the transition from pluripotent to neural-restricted stem cell. Our analysis showed that >90% of the promoters are in common between the two cell types, while approximately half of the enhancers are cell-specific and account for most of the epigenetic changes occurring during neural induction, and most likely for the modulation of the promoters to generate cell-specific gene expression programs. Interestingly, the majority of the promoters activated or up-regulated during neural induction have a “bivalent” histone modification signature in ESCs, suggesting that developmentally-regulated promoters are already poised for transcription in ESCs, which are apparently pre-committed to neuroectodermal differentiation. Overall, our study provide a collection of differentially used enhancers, promoters, transcription starts sites, protein-coding and non-coding RNAs in human ESCs and ESC-derived NESCs, and a broad, genome-wide description of promoter and enhancer usage and gene expression programs occurring in the transition from a pluripotent to a neural-restricted cell fate. ESCs (H9 NIH code WA09, ISL1 Ds-Red) were kindly provided by the group of K.R. Chien. Neural differentiation was induced by the method of embryoid bodies following a published protocol [1]. Briefly, 4-days embryoid bodies were transferred to polyornithine-coated dishes and propagated in N2-supplemented DMEM/F12 (Invitrogen). Total RNA was extracted from 1-2x10^6 cells from three different cultures of ESCs and NESCs, transcribed into biotinylatedcRNA and hybridized onto GeneChip® HG-U133 Plus 2.0 Arrays (Affymetrix) according to the protocol supplied by the manufacturer (Affymetrix, Santa Clara, CA).

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Tnfaip2/Exoc3 controls exit from pluripotency by mediating lipid droplet formation and FA-induced differentiation

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