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PGE2-EP3 axis controls brown adipose tissue development through stabilization of WTAP protein

ABSTRACT: PGE2-EP3 axis controls brown adipose tissue development through stabilization of WTAP protein

PROVIDER: PRJNA830835 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18888657_1.fastq.gz	Fastqsanger.gz
	SRR18888657_2.fastq.gz	Fastqsanger.gz
	SRR18888658_1.fastq.gz	Fastqsanger.gz
	SRR18888658_2.fastq.gz	Fastqsanger.gz
	SRR18888659_1.fastq.gz	Fastqsanger.gz

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PGE2-EP3 axis controls brown adipose tissue development

Project description:PGE2/EP3 signaling and m6A modification is required for brown adipocyte differentiation and BAT development, but the underlying mechanisms involved remain to be elucidated. The Arraystar mousen M6a-MRNA&lncRNA Epitranscriptomic microarray analysis was performed on mouse brown preadipocytes with or without EP3 deletion.

2022-04-18 | GSE200924 | GEO

PGE2-EP3 axis controls brown adipose tissue development

Project description:PGE2-EP3 axis controls brown adipose tissue development

| PRJNA827444 | ENA

PGE2-EP3 axis controls brown adipose tissue development through stabilization of WTAP protein

Project description:By conducting CUT&TAG, we reported that brown adipogenesis induction markedly increased ZFP410 occupancy on chromatin. GO analysis revealed that genes containing the ZFP410-bound peaks were enriched in fat cell differentiation. Consistently, binding signals of ZFP410 on the promoter regions of CHD4 as well as brown genes such as Pgc-1a, Prdm16 and Cyto C were markedly increased in differentiated pre-adipocytes compared to those in control cells.

2022-04-25 | GSE201304 | GEO

PGE2-EP3 axis promotes brown adipose tissue formation through stabilization of WTAP RNA methyltransferase

Project description:Brown adipose tissue (BAT) functions as a thermogenic organ and is negatively associated with cardiometabolic diseases. N6-methyladenosine (m6A) modulation regulates the fate of stem cells. Here, we show that the prostaglandin E2 (PGE2)-E-prostanoid receptor 3 (EP3) axis was activated during mouse interscapular BAT development. Disruption of EP3 impaired the browning process during adipocyte differentiation from pre-adipocytes. Brown adipocyte-specific depletion of EP3 compromised interscapular BAT formation and aggravated high-fat diet-induced obesity and insulin resistance in vivo. Mechanistically, activation of EP3 stabilized the Zfp410 mRNA via WTAP-mediated m6A modification, while knockdown of Zfp410 abolished the EP3-induced enhancement of brown adipogenesis. EP3 prevented ubiquitin-mediated degradation of WTAP by eliminating PKA-mediated ERK1/2 inhibition during brown adipocyte differentiation. Ablation of WTAP in brown adipocytes abrogated the protective effect of EP3 overexpression in high-fat diet-fed mice. Inhibition of EP3 also retarded human embryonic stem cell differentiation into mature brown adipocytes by reducing the WTAP levels. Thus, a conserved PGE2-EP3 axis promotes BAT development by stabilizing WTAP/Zfp410 signaling in a PKA/ERK1/2-dependent manner.

| S-SCDT-EMBOJ-2021-110439 | biostudies-other

Effect of PGE2 pathway antagonists on APCmin/+ small intestine polyps

Project description:While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well-established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small molecule antagonists of single EP receptors, the COX-2 inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8+ T cells in vitro as compared to single EP antagonists. CD8+ T cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased TME lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC)min+/- spontaneous colorectal tumor model, compared to celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small molecule dual EP2/EP4 antagonist.

2023-08-21 | GSE229806 | GEO

Single-nucleus transcriptome analysis of interscapular brown adipose tissue (iBAT) in Wtapflox/flox and BAT-specific Wtap knockout (BKO) mice

Project description:Purpose: Through Single-nucleus transcriptome analysis, we aim to characterize the changes of cell heterogeneity in iBAT obtained from Wtap-BKO mice compared with that in Wtapflox/flox mice. Methods: Nuclei were isolated from iBAT of Wtap flox/flox and Wtap-BKO mice at 8 weeks old. Each sample was pooled from 4 mice for each group. Conclusion: The Single-nucleus transcriptomes of iBAT in Wtapflox/flox and BKO mice were characterized.

2022-10-20 | GSE202630 | GEO

PGE<sub>2</sub> -EP3 axis promotes brown adipose tissue formation through stabilization of WTAP RNA methyltransferase.

Project description:Brown adipose tissue (BAT) functions as a thermogenic organ and is negatively associated with cardiometabolic diseases. N6 -methyladenosine (m6 A) modulation regulates the fate of stem cells. Here, we show that the prostaglandin E2 (PGE2 )-E-prostanoid receptor 3 (EP3) axis was activated during mouse interscapular BAT development. Disruption of EP3 impaired the browning process during adipocyte differentiation from pre-adipocytes. Brown adipocyte-specific depletion of EP3 compromised interscapular BAT formation and aggravated high-fat diet-induced obesity and insulin resistance in vivo. Mechanistically, activation of EP3 stabilized the Zfp410 mRNA via WTAP-mediated m6 A modification, while knockdown of Zfp410 abolished the EP3-induced enhancement of brown adipogenesis. EP3 prevented ubiquitin-mediated degradation of WTAP by eliminating PKA-mediated ERK1/2 inhibition during brown adipocyte differentiation. Ablation of WTAP in brown adipocytes abrogated the protective effect of EP3 overexpression in high-fat diet-fed mice. Inhibition of EP3 also retarded human embryonic stem cell differentiation into mature brown adipocytes by reducing the WTAP levels. Thus, a conserved PGE2 -EP3 axis promotes BAT development by stabilizing WTAP/Zfp410 signaling in a PKA/ERK1/2-dependent manner.

| S-EPMC9379545 | biostudies-literature

m6A MeRIP-Seq of interscapular brown adipose tissue (iBAT) in Wtapflox/flox and BAT-specific Wtap knockout (BKO) mice

Project description:Purpose: Through mRNA m6A-profiling, we aim to characterize the mRNA m6A changes in iBAT obtained from Wtapflox/flox and Wtap-BKO mice. Methods: Total RNA was extracted using Tripure Isolation Reagent (Roche, Mannheim, Germany) from iBAT of Wtap flox/flox and Wtap-BKO mice at 8 weeks old. Each sample (300 μg total RNA) was pooled from 8 mice for each group. Poly(A)+ RNA was purified using Dynabeads™ mRNA Purification Kit (Invitrogen) following the manufacturer’s instructions. Fragmented mRNA was incubated with m6A antibody (Synaptic System, 202003) for immunoprecipitation. Then, immunoprecipitated mRNAs or Input was used for library construction with NEBNext ultra RNA library prepare kit for Illumina (New England Biolabs).The library preparations were sequenced on an Illumina Novaseq 6000 platform with a paired-end read length of 150 bp according to the standard protocols. The m6A peaks were detected by exomePeak R package (version 2.16.0). The motif search was detected by HOMER(version 4.9.1). Conclusion: The iBAT mRNA m6A profiles in Wtapflox/flox and BKO mice were characterized.

2022-10-19 | GSE202668 | GEO

Binding motif analysis of METTL3，WTAP in METTL3，WTAP overexpressed Human 293T cells

Project description:label the cells overexpressed Myc tagged METTL3 and Flag tagged WTAP with 4-SU, the RNA bound by METT3,WTAP can be got by Myc or Flag IP followed by RNA isolation by using the TRIzol (Invitrogen) reagent by following the company manual.the RNA was then used for library preparation using a TruSeq™ RNA Sample Prep Kit v2 (Illumina, San Diego, CA, USA) according to the manufacturer’s protocol.The libraries were sequenced using HiSeq2000 (Illumina) in single-read mode, creating reads with a length of 50 bp. Sequencing chemistry v2 (Illumina) was used and samples were multiplexed in two samples per lane. discovery of the binding motif of METTL3，WTAP in METTL3，WTAP overexpressed Human 293T cells

2014-01-16 | E-GEOD-50580 | biostudies-arrayexpress

Systemic metabolic alterations correlate with islet-level prostaglandin E2 production and signaling mechanisms that predict beta-cell dysfunction in a mouse model of type 2 diabetes

Project description:The transition from β-cell compensation to β-cell failure is not well understood. Previous works by our group and others have demonstrated a role for Prostaglandin EP3 receptor (EP3), encoded by the Ptger3 gene, in the loss of functional β-cell mass in T2D. The primary endogenous EP3 ligand is the arachidonic acid metabolite, prostaglandin E2 (PGE2). Pancreatic islet EP3 expression, expression of PGE2 synthetic enzymes, and/or PGE2 excretion itself have all been shown as up-regulated in primary mouse and human islets isolated from animals or human organ donors with established T2D as compared to non-diabetic controls. In this study, we took advantage of a rare and fleeting phenotype in which a subset of Black and Tan BRachyury (BTBR) mice homozygous for the Leptinob/ob mutation—a strong genetic model of T2D—were entirely protected from fasting hyperglycemia even with equal obesity and insulin resistance as their hyperglycemic littermates. Utilizing this model, we found numerous alterations in full-body metabolic parameters in T2D-protected mice (e.g., gut microbiome composition, circulating pancreatic and incretin hormones, and markers of systemic inflammation) that correlate with improvements in EP3-mediated β-cell dysfunction.

2021-09-09 | PXD022624 | Pride

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