Elucidating the molecular mechanisms underlying brite adipocyte specification and activation

Informations projet

BRITE

N° de convention de subvention: 803491

DOI

10.3030/803491

Projet clôturé

Date de signature de la CE 12 Février 2019

Date de début 1 Mars 2019

Date de fin 29 Février 2024

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 552 620,00

Contribution de l’UE

€ 1 552 620,00

Coordonné par

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Switzerland

Periodic Reporting for period 4 - BRITE (Elucidating the molecular mechanisms underlying brite adipocyte specification and activation)

Période du rapport: 2023-09-01 au 2024-02-29

Résumé du contexte et des objectifs généraux du projet

Brown adipocytes dissipate energy through adaptive thermogenesis. In humans, classical brown adipose tissue (BAT) largely disappears early in life, but cold exposure can induce the formation of brown-like adipocytes within white adipose tissue (WAT), known as brite (brown-in-white) adipocytes. Increased BAT activity elevates energy expenditure and is associated with leanness. Thus, inducing brite adipocytes represents a potential therapeutic approach for treating obesity and related metabolic diseases. However, the molecular mechanisms underlying the specification and activation of brown and brite adipocytes in vivo remain poorly understood.

Using advanced techniques and reporter mice, we generated paired single-mouse datasets and performed an integrative multimodal analysis of five histone marks in beige, brown, and white adipocytes from three distinct mouse adipose tissue depots. Our analysis identified enhancers that distinguish adipocytes by their tissue of origin, differentiating beige from brown adipocytes. Additionally, ablation studies of beige adipocytes revealed that white adipocytes in inguinal adipose tissue and beige adipocytes utilize similar enhancer sets, both preparing thermogenic genes for expression. Conversely, adipocytes from epididymal adipose tissue actively repressed thermogenic master regulators and exhibited a distinct enhancer profile compared to white adipocytes from inguinal tissue. These paired multimodal datasets provide a comprehensive resource for further exploration of the mouse adipocyte epigenome, potentially facilitating the discovery of regulatory elements that govern adipocyte identity and gene regulation.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We have generated and analyzed gene expression and histone modification data of bulk and single cell adipose tissue from cold exposed and cold recovered mice with age matched controls. We observe a dynamic shift in activating and repressive epigenetic marks with cold exposure and a return to a ground state with recovery. We see a similar trend on gene expression level. Further, we observe an age and/or body weight effect on RNA expression level.
We have now also collected biological samples from reporter mice for Ucp1+ and Adipoq+ from cold exposure, recover, re-exposure, thermoneutrality and aged matched appropriate controls and are processing these as the prior samples.

We are finalising the first single cell epigenetic characterisation of the mouse adipose tissue. Together we will compile a comprehensive epigenetic atlas of the mouse adipose tissues during cold exposure and normal conditions.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Utilizing the cutting-edge CUT&Tag method and NuTRAP mice, we generated paired single-mouse datasets, allowing us to perform an integrative multimodal analysis of five histone marks in beige, brown, and white adipocytes from three distinct mouse adipose tissue depots. This comprehensive analysis enabled us to uncover that enhancers can distinguish adipocytes based on their tissue of origin, with H3K4me1 deposition playing a critical role in differentiating beige from brown adipocytes.

Our findings were further substantiated by experiments involving diphtheria toxin-mediated ablation of beige adipocytes. These experiments revealed that white adipocytes in inguinal adipose tissue and beige adipocytes did not employ distinct enhancer sets; instead, both types of adipocytes prepared thermogenic genes for expression. In stark contrast, adipocytes from epididymal adipose tissue were found to actively repress thermogenic master regulators, exhibiting a distinct enhancer profile when compared to white adipocytes from inguinal tissue.

These paired multimodal data provide a valuable and extensive resource for the further exploration of the mouse adipocyte epigenome. This resource is expected to significantly enhance our understanding of the regulatory elements that govern adipocyte identity and gene regulation, potentially leading to breakthroughs in metabolic research and therapeutic strategies for metabolic diseases. By elucidating the epigenetic landscape of different adipocyte types, our study lays the groundwork for future investigations into the molecular mechanisms driving adipocyte differentiation and function.

NuTRAP (Nuclear Tagging and Translating Ribosome Affinity Purification) allows simultaneous cell-typ