H2020Индивидуална стипендия2020–2022

EPIDNA · Structural investigation of interplay between epigenetics, transcriptional regulation and DNA damage

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2020-04-01 → 2022-03-31
Финансиране от ЕС: 160 932 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Епигенетичната регулация и повредите на ДНК се изследват чрез анализи на структури като нуклеозомите. Това помага да се разбере как се изразява и поддържа генетичната информация, както и какви са механизмите зад мутациите при COVID-19.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Structural investigation of interplay between epigenetics, transcriptional regulation and DNA damage

The project’s main objective was to characterize selected structural aspects of epigenetic regulation and its coupling to DNA modification. In particular, the following questions were addressed: - possible obstruction of DNA repair due to the presence of nucleosomes; - direct changes in the regulation of gene expression caused by oxidative stress; - structural response of nucleosome core particles to the chromatin remodeling machinery; - possible functional roles of histone lipidation, a newly discovered epigenetic marker. These questions contribute to our fundamental understanding of how genetic information is expressed, maintained, and regulated. The structural approach employed in this project provides important context for often serendipitous experimental observations, one that allows for a rational design of future experiments and therapeutic interventions. Moreover, since the timeline of the project coincided with the COVID-19 pandemic, significant efforts and resources were redirected to address this urgent issue using the unique techniques at our disposal. These additional lines of research investigated the following questions: - a possible evolutionary advantage of the A222V point mutation, dominant in Spain in summer 2020 and then rediscovered in a sub-strain of Delta; - the mutational pathway followed during the virus’ zoonotic transition from bat to human; - the differences in the structural properties conferred by the collection of mutations accumulated by the Omicron strain; - a review of methodological and applicational advances in the computational research on COVID-19. Here, the research performed within the project aimed to further our understanding of the driving forces behind the pandemic, understand the pharmacological strategies deployed to mitigate it, and calibrate new methods for massive, rapid and accurate investigation of the consequences of protein mutations.

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

Цел на проекта

In eukaryotic cells, gene expression is regulated by a complex interplay between a number of factors, from large-scale chromatin accessibility to inducible enhancers or repressors to local DNA modifications, changes in nucleosome architecture and specific histone markers. These finely tuned factors coordinate embrional development, response to stimuli and changes in cell fate. At the same time, this regulatory network has to robustly accommodate random events, most notably the presence of DNA damage and the action of DNA repair factors. While recent reports suggest this interplay is not always smooth, our mechanistic understanding of the underlying processes is severely limited, highlighting the need for quantitative approaches that will yield predictive models.In this proposal, I plan to investigate three aspects of this interplay that recently came into the spotlight. Firstly, an integrative computational and experimental approach will be used to quantify the positioning effect resulting from a range of common DNA modifications: regulatory base variants that can be used to enforce specific nucleosome patterns, and damage byproducts that would thereby interfere with DNA repair through altered exposure to the environment. Secondly, a number of transcription factors will be systematically assessed to detect ones sensitive to the presence of the most common oxidative lesion, 8-oxoguanine, to identify possible direct cross-talk between oxidative stress and transcriptional regulation at oxidative hot spots. Finally, a multiscale quantum/classical study will explore the thermodynamics, mechanism of formation and possible nucleosomal locations of covalent histone-DNA cross-links that were recently postulated to both mediate the regulatory role of 5-formylcytosine and accelerate strand scission at abasic sites.

Оригинален текст от CORDIS (на английски).

Участници

FUNDACIO INSTITUT DE RECERCA BIOMEDICA (IRB BARCELONA) · BarcelonaКоординаторИспания