Projects

To sustain life and its quality on Earth, the EU has established several initiatives for the implementation of the Green Deal: Zero Pollution Action Plan, Farm to Fork and Green Deal Industrial Plan, among many others. All of these require significant innovation, based on new knowledge and skills – research, training and education – coupled with industry adaptation, civil society engagement and smart regulation, which is a challenge globally. More importantly, we need significantly more people who can carry out this innovation. The main objective of “Innovative Chemistry and Biotechnology for a Sustainable Future” (INNOCHEMBIO) is to train future experts of sustainable chemistry and biotechnology, helping Europe to take the next steps in the green transition. The solutions and trained experts can reduce the environmental impact of the chemical and agricultural industries, offer eco-friendly analytical techniques, and assess the safety of new materials. This will be achieved through interdisciplinary research projects in an international research environment, collaboration with the industry, the public sector and the civil society, via a comprehensive quadruple-helix based training programme. As a result, our graduates will not only become experts in their respective fields, but leaders and spokespersons. Eventually, through dedicated career planning, we provide skilled workforce to all 4 sectors of the helix. INNOCHEMBIO is an international consortium led by TalTech, with over 100 years of experience in chemistry and biotechnology research and training. INNOCHEMBIO will achieve its objectives by recruiting 15 PhD candidates in up to two calls offering fellowships for 48 months. During this period, the candidates will receive discipline specific training both in Estonia and abroad by working on their research project; broader training through courses offered at TalTech and by our partners; and experience working in the private sector.

Europe still sees a quarter of the world's cancer cases each year, making cancer the second leading cause of death and illness in the region after cardiovascular diseases. Unless we take decisive action, lives lost to cancer in the EU are set to increase by more than 24% by 2035, making it the leading cause of death in the EU. Cross-border collaboration can address this challenge by combining data from various modalities and sources, extracting meaningful insights to deepen our understanding of cancer. However, ethical, legal, and national regulations, along with data access processes, including differing interpretations of the EU GDPR create significant hurdles. Technical interoperability issues across European cancer RIs, and patients' and citizens' rights to control who uses their personal information and for what purposes further complicate data sharing. The project will provide European researchers, SMEs, and innovators with a decentralized collaborative network, “UNCAN-CONNECT,” for cancer research. It consists of both technical components, a governance, compliance, and operational framework based on the UNCAN blueprint, with the goal of operationalizing it. The objective is to facilitate access to cancer data, promote open science, and revolutionize cancer research and treatment by co-creating an open-source federation of federations platform. It will be developed using specific use cases focused on six major cancer types: Paediatric, Lymphoid malignancies, Pancreatic cancer, Ovarian, Lung, and Prostate cancers and active collaboration with a diverse range of stakeholders,including researchers, SMEs, industrial end users, and citizens. It will build on existing European RIs such as BBMRI as well as initiatives like EOSC4CANCER, CanSERV, EUCAIM, to enable seamless storage, access, sharing, and processing of data across Member States and associated countries. This approach will foster interoperability and collaboration, accelerating progress in cancer research. This action is part of the Cancer Mission clusters of projects 'Understanding' established in 2022.

Neural plasticity is the ability of nervous system to change its activity in response to stimuli by reorganizing its structure, functions, or connections and this is the main cellular basis for memory. Activity-regulated genes play crucial roles in the formation of neuronal plasticity, and dysregulation of this process gives rise to various nervous system disorders. The neurotrophin BDNF is among the best-studied activity-regulated genes, and its polymorphisms are associated with impairments in human cognition. Our results also place the basic helix-loop-helix transcription factor TCF4, that is implicated in a variety of psychiatric and autism spectrum disorders, to the group of activity-regulated transcription factors. The aim of this project is to study gene regulation in intellectual disability and autism spectrum disorders with emphasis on disease-associated transcription factors TCF4, SATB2, FOXP1, and neurotrophin BDNF for finding new drug targets.

Projekt OptimaMind keskendub ajapiiranguga söömisele, et parandada aju tervist ja võidelda vananemisega kaasnevate väljakutsetega. Ajalooliselt oli inimeste juurdepääs toidule sageli juhuslik, muutes vahelduva paastumise (teise nimega aeg-restrikteeritud söömise (TRE)) elu loomulikuks osaks. See ajalooline kontekst loob aluse TRE võimalike eeliste mõistmiseks tänapäeval, eriti kognitiivse tervise kontekstis. On näidatud, et TRE kutsub esile adaptiivseid molekulaarseid muutusi, mis kaitsevad rakuressursse, parandades samal ajal füüsilist ja kognitiivset jõudlust. Sellised muutused hõlmavad süsteemse põletiku vähenemist ja raku antioksüdantide potentsiaali suurenemist. Üks TRE mõju näidetest on beeta-hüdroksübutüraadi (BHB), ketoonkeha, mis parandab kognitiivseid funktsioone, tootmine. Maksas toodetud BHB on oluline energiasubstraat, millel on võrreldes teiste energiaallikatega kasulikumaid omadusi. Ja vastupidi, sagedane toidutarbimine ja vähene füüsiline aktiivsus võivad pärssida BHB tootmist, vähendades seega selle positiivset mõju. Projekti OptimaMind eesmärk on uurida erinevate meetodite abil TRE mõju kognitiivsete funktsioonide biomarkeritele, eriti vananevas elanikkonnas. Kavandatavas projektis kasutatakse Euroopas olemasolevaid biopankade proove ja erinevaid paastuprotokolli kohordi andmeid, et uurida neuroprotektiivseid biomarkereid erinevates populatsioonides. Oodatavad tulemused hõlmavad uusi teadmisi TRE-st kui mittefarmakoloogilisest strateegiast kognitiivse pikaealisuse suurendamiseks ja dementsuse ennetamiseks. Projekti eesmärk on ka teavitada tervishoiuteenuse osutajaid ja avalikkust praktilistest tõenduspõhistest strateegiatest aju tervise säilitamiseks. OptimaMind mõjutab rahvatervise soovitusi, kliinilisi tavasid ja heaolutööstust, mille eesmärk on lõpuks parandada kognitiivset tervist ja elukvaliteeti vananevas elanikkonnas.

Neuronal plasticity, the ability of the nervous system to adapt to internal or external stimuli, is a fundamental property that underlies brain development, learning, memory, and resilience to neurodegenerative disorders. At the molecular level, neuronal plasticity depends on the activation of neuronal activity-regulated genes (nARGs), a process tightly controlled by enhancer regions—short regulatory DNA sequences. Recent findings reveal that active enhancers produce enhancer-derived RNAs (eRNAs), which may play crucial roles in gene regulation through complex interactions with DNA, RNA, and proteins. Despite their potential significance, the function of eRNAs in neuronal activity remains poorly understood due to their transient nature and technical challenges in studying them. This project aims to develop innovative experimental approaches to unravel the role of eRNAs in nARG activation. Using rodent primary neuronal culture —a well-established model for studying neuronal plasticity—the project will systematically analyze eRNA responses to external stimuli with high temporal resolution. Comprehensive sequencing technologies will be combined to characterize the molecular features of eRNAs. These data will be complemented by epigenomic profiling to correlate enhancer activity with transcriptional dynamics. The project will also investigate potential links between eRNA features and neurodegenerative disease-associated mutations, providing insights into how brief stimuli-related gene activation may contribute to disease phenotypes. Together, these studies will create a framework for understanding the regulatory roles of eRNAs in neuronal plasticity and their broader implications for brain development and disorders.

Enhancers are short distal cis-regulatory DNA regions that drive expression of a gene. However, enhancers do not function exclusively as DNA entities. Activated enhancers are transcribed by RNA polymerase II (RNAPII), which produces enhancer-derived RNAs (eRNAs). Production of eRNA creates additional trans-regulatory mechanisms facilitated by DNA-RNA, RNA-RNA, or protein-RNA interactions. Due to eRNAs’ fast degradation rates, and lack of robust and standardized sequencing methods, reports about the molecular nature of eRNA molecules and their processing are conflicting, making mechanisms of gene regulation by eRNA controversial. Even less is known about co- and post-transcriptional processing of eRNA. This project aims to overcome the controversy and fill the knowledge gap by studying a well-defined experimental system, cultured rat cortical neurons, and activation of immediate-early gene (IEG) response, perturbing the core eRNA endonuclease and combining this with eRNA-tailored sequencing, computational and biochemical methods. The developed integrative approach will reveal molecular features of eRNA molecules and their precursors genome-wide, opening the opportunity to study eRNA biogenesis to further understand molecular mechanisms behind the eRNA-mediated gene regulation.

Formation of new synapses, and alteration of the strength and stability of existing synapses are regarded as the main cellular basis for memory and long-term behavioral adaptations. Neuronal activity-regulated gene expression plays a crucial role in synaptic development and function, and its deregulation gives rise to various nervous system disorders. Knowledge about the regulatory mechanisms of activity-dependent gene expression is important both for understanding of nervous system function and for finding new drug targets. The aim of this project is to study the molecular mechanisms of neuronal activity-regulated gene expression, including transcription, translation and posttranslational modifications, in the nervous system health and disease. The studies are focused on two genes, the neurotrophin BDNF and the basic helix-loop-helix transcription factor TCF4.

"Pitt-Hopkins syndrome is a cognitive functional disorder, caused by a de novo genetic mutation of one allele of the transcription factor 4 (TCF4) gene. It has been reported that postnatal restoration of TCF functions in Pitt-Hopkins syndrome animal model (partially) rescues the phenotype, indicating that therapeutic approaches increasing TCF4 levels or activity might also help patients. It has also been reported that inhibiting histone deacetylase activity increases TCF4 transcriptional activity and rescues memory deficiencies associated with TCF4 haploinsufficiency in a mouse model. These effects are likely conveyed by some TCF4 co-repressor, such as ETO/RUNX1T1 recruiting HDACs. However, HDAC inhibitors have a very broad effect on the cellular transcription and can cause various side-effects. Here, we hypothesize that by modulating the activity of specific TCF4 co-activators or co-repressors or their interaction with TCF4 could increase TCF4-dependent transcription, thus alleviating the symptoms of Pitt-Hopkins syndrome and have less side effects for the patients. To this end, we pursue to thoroughly identify the co-regulators participating in TCF4-dependent transcription, and to find means to modulate their activity. The specific aims are as follows: (1) Identify the co-regulatory proteins of different TCF4 protein isoforms. (2) Determine the mechanism of action and the interacting regions between TCF4 and co-regulatory proteins. (3) Develop means to modulate the transcriptional activity or binding of the TCF4 co-regulatory proteins."

The aim of this project was to investigate the regulation of stimuli-activated neuronal enhancers through enhancer-derived RNA (eRNA), addressing the challenge posed by the unstable and transient nature of eRNAs. We combined advanced next-generation sequencing techniques with molecular biology assays to gain a mechanistic understanding of eRNA function in activity-dependent gene expression. The project's critical task was establishing a robust genome-wide method to precisely define the eRNA 5’ to 3’ end sequence. We optimized the MAPcap method, which emerged as the preferred technique for transcription start site (TSS) detection due to its low sequencing depth requirement, compatibility with previously collected RNA samples, and ease of integration into research workflows. As model systems we selected primary rat cortical neurons and Neuro2A mouse neuroblastoma cells. For both systems, we tested and optimized cultivation, treatment, and subcellular fractionation protocols. We also established RT-qPCR assays to validate eRNAs and immediate-early genes. To prepare for the functional validation of eRNAs, we established a complete procedure encompassing in vitro transcription, biochemical pull-down assays, and mass spectrometry analysis. This workflow will be applied after we complete the analysis of our NGS datasets and define eRNAs of interest. In conclusion, this project has successfully established methods and generated data that advance our understanding of eRNA roles in neuronal gene regulation. The outcomes of this research pave the way for significant discoveries in neurobiology and provide a robust platform for future studies. The support from this grant has been instrumental in achieving these results, promising impactful contributions to the field.

This project took a closer look at how BDNF, an important protein usually studied in neurons, is regulated in heart cells and in special brain cells called astrocytes. First, we figured out signals that “switch on” BDNF, such as noradrenaline (similar to adrenaline), and studied DNA regions that help controlling this switch, specifically in cardiac cells. We then focused on astrocytes, a kind of brain cell that supports neurons, among other functions. We observed that when neurons and astrocytes are maintained together and neurons are activated, astrocytes respond by producing more BDNF. BDNF is an actively studied protein, given its critical roles in the central nervous system and especially in neurons. More recently, BDNF expression and function have been studied in other cell types as well, revealing a larger spectrum of roles for this neurotrophin. Furthermore, its dysregulation in several pathological conditions make it an interesting target for therapeutic interventions. The results obtained in the frame of this project are therefore interesting to the neurotrophin community, and more broadly to the neurobiology and cardiac biology fields, and provide the fundamental knowledge required to design and implement treatment strategies. Different methodologies needed to be put in place an optimized in order to achieve the goals of this project. As a result, these are now part of the group’s diverse tool kit and can be implemented to address several of our research questions, which I find to be an important outcome of the project. Finally, the successful defence of the MSc thesis of a co-supervised student is an important milestone and a key achievement associated with this grant.

The aim of the centre is to translate the rapid progress in the field of genomics and other “-omics” technologies into improved understanding of molecular and evolutionary mechanisms of disease as well as improved prevention, diagnosis and clinical care. The Centre integrates 12 research units from University of Tartu, Estonian Biocentre and Tallinn University of Technology.

The project is focused on developing molecular diagnostics tools for early detection of schizophrenia. The research program of SZ_TEST will include three interrelated lines of research: 1: Deciphering molecular mechanisms of schizophrenia. 2: Identifying molecular biomarkers for early detection of schizophrenia. 3: Developing reliable protocols for diagnostic use of newly identified biomarkers in clinical settings.