HEИндивидуална стипендия2023–2025

M-Y-cro · Metabolism-YEATS-crosstalk: Elucidating metabolic dependencies of epigenetic YEATS action

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период: 2023-08-01 → 2025-07-31
Финансиране от ЕС: 183 601 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Връзката между метаболизма и епигенетиката се проучва чрез взаимодействието на YEATS протеините с метаболитните ензими. Разбирането на тези процеси помага да се изясни как се развиват различни заболявания, включително някои видове рак.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Metabolism-YEATS-crosstalk: Elucidating metabolic dependencies of epigenetic YEATS action

Cells and ultimately organisms tightly regulate essential pathways to support complex biological processes such as homeostasis, growth, and differentiation. Increasing evidence suggests that these pathways operate in a highly integrated and coordinated manner, rather than functioning in isolation. The overarching aim of this proposal was to deepen our understanding of the mechanistic regulation of key cellular pathways, with a particular focus on the interplay between metabolism and epigenetics (i.e. chromatin metabolism). Building on previous findings and expertise from our laboratory - specifically the discovery of a functional interaction between the folate enzyme MTHFD1 and the histone acetylation reader protein BRD4 - we hypothesized that similar metabolism-centric regulatory relationship(s) may exist with YEATS domain-containing reader proteins, which recognize histone acylation marks. Moreover, although dysregulation of YEATS proteins has been linked to various diseases, most notably in different types of cancer, their overall function, particularly the context and consequences of their histone acylation reading ability, remain only partially understood. Thus, to investigate potential functional relationships, we proposed a series of work packages (WPs) within the proposal: While WP1 focused on characterizing the baseline functions of YEATS proteins under various metabolite-enriched conditions, WP2 aimed to identify functional interactions between YEATS proteins and metabolic enzymes, that require further in-depth characterization, as proposed in WP3. To address these WPs, we planned to develop YEATS-perturbation-dependent fluorescent reporter systems, that could respond upon genetic or chemical perturbation, thus linking these phenotypes to YEATS protein function. In the absence of suitable chemical tool compounds for all YEATS proteins, we aimed to generate dTAG-YEATS cell lines that enable targeted protein degradation upon incubation with the corresponding PROTAC.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Metabolism and gene regulations act in concert to shape cellular identity and plasticity. One major line of crosstalk occurs through metabolites such as acyl-CoAs, which are inscribed on histones as posttranslational modifications (PTMs) to be subsequently recognised by reader proteins, resulting in initiation of specific transcriptional programs. The increasing identification of novel PTMs necessitates thorough characterisation, however still remain largely underexplored. For instance, the presence of non-acetyl acyl-Lys PTMs such as crotonylation with YEATS-reader proteins identified to bind these PTMs suggests complex gene regulation programs. However, despite the clinical relevance of YEATS-proteins in various cancers, little is known about their acyl-reading activity and transcriptional consequences. Therefore, this proposal aims to close multiple knowledge gaps regarding overall function and mechanism of the metabolism/acyl-PTM/YEATS communication axis. Considering the metabolic context, I furthermore propose epigenetic YEATS action to be determined by direct interactions with metabolic proteins. Thus, I will first establish an inducible YEATS-degradation platform to characterise the genomic context under various acylate conditions. Next, I will implement a fluorescence-based cell reporter system, which shall reveal putative interactors upon transfection with a CRISPR-KO library targeting metabolic enzymes. Lastly, hits will be biophysically characterized, their metabolic impact within the epigenetic context determined and co-dependencies on relevant cancer cell lines tested. The interdisciplinary approach entailing state-of-the-art chemical and molecular biology tools will be combined with high-throughput screening methods and bioinformatic analyses. Besides elucidating general principles of the metabolism-YEATS epigenetics crosstalk, the results will provide valuable information for novel therapeutic avenues by exploiting identified co-dependencies.

Оригинален текст от CORDIS (на английски).

Участници

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH · WienКоординаторАвстрия