ONGOING RESEARCH PROJECTS
The impact of early life stress: from brain to germline
Current research focuses on the identification of the ensemble of epigenetic factors and mechanisms in germ cells and the brain associated with the expression and inheritance of acquired traits across generations in mice. We examine the causal involvement of these factors and mechanisms in mental and physical disorders, and their possible transmission from parent to offspring and we study of their modes of induction and maintenance. The long-term objective is to reach sufficient understanding of the mechanisms of epigenetic inheritance to help the design and development of potential diagnostic and therapeutic tools for trauma patients in the clinics.
Some of the current projects are:
CHROMATIN & THE BRAIN: A MULTIOMICS STORY
The stress response is primarily mediated by secretion of glucocorticoids, which can persistently alter chromatin. This research project focuses on how stress pathway activation can acutely and persistently modify chromatin in stem cell-derived neurons. The relationship between different molecular layers and the expression of neuronal responses induced by exposure is investigated using multiomics methods. The results are expected to provide insight into the role of molecular memory in the brain in relation to stress.
SPERM CHROMATIN: MORE THAN JUST A DNA CARRIER?
This project explores how environmental factors impact chromatin modifications in sperm and whether these alterations are inherited by the embryo post-fertilization. Chromatin, the DNA-protein complex, plays a crucial role in genetic regulation. By studying the interplay between an altered diet and chromatin in sperm and the early embryo, the project aims to identify mechanisms influencing heritable traits. This research delves into the dynamic nature of chromatin modifications and their contribution to epigenetic inheritance. To pursue this project, we use a combination of sequencing technologies such as CUT&Tag, ATAC-seq and single-embryo RNA-seq.
EPIGENETIC MEMORY AND INHERITANCE IN THE GERMLINE
Information about early life events can be transmitted from exposed parent to the offspring via the parental germline long after the original exposure. How this information persists and can be passed on remains poorly understood. This project studies the mechanisms by which such “cellular memory” and its transmission is possible using a multidimensional approach to characterize and manipulate germ cells. The approach integrates CRISPR-editing in germ stem cells, three-dimensional testicular cultures and in vivo transplantation.
PATERNAL STRESS & HEMATOPOIESIS IN MICE
In adult mice, exposure to chronic stress increases hematopoietic stem and progenitor proliferation and worsens atherosclerotic symptoms. Whether hematopoiesis is also affected by early life stress is not well known. This research examines the long-term impact of early life stress on hematopoiesis in mice and their offspring. It also addresses the question of the reversibility of the effects of early life stress and preventative potential of environmental enrichment.
EXPLORING SOMA-TO-GERMLINE COMMUNICATION
This research project explores the potential role of extracellular vesicles (EVs) in soma-to-germline communication. EVs are small membrane-enclosed structures released by cells into the extracellular space that carry active molecules playing and active role in intercellular communication. The project examines circulating EVs in blood and the possibility that they may allow the transfer of information from the periphery to germ cells in males. This is studied in the context of early life stress.
SUSCEPTIBILITY OF THE GERMLINE TO STRESS
Exposure to childhood trauma is known to be associated with epigenetic and transcriptional changes in sperm or semen of men. Using live mice and cellular models, this project examines whether and how early life stress affects molecular integrity of germline stem cells, the precursors of reproductive cells, and the consequences for mature gametes.
GENOMIC PROXIMITY: A BRAIN ODYSSEY
Brain cells fulfill an important role in the processing and storage of information during the entire lifetime. In this project, we study whether and how experience-dependent regulatory memory results in stable changes in chromatin structure and organization in brain cells. To study these questions, we exploit a mouse model of early life chronic stress developed in the lab to examine how the regulatory genome in the adult brain, particularly 3D genome organization, is persistently remodeled by such salient experiences. We test the causal link between chromatin looping and activity-dependent gene expression in vitro and in vivo using state-of-the-art experimental strategies.
EXTRACELLULAR RNA & NOVEL BIOMARKERS FOR PRECISION MEDICINE
This research explores extracellular RNA (exRNA) biogenesis and its role in cell-to-cell communication The purpose is to identify novel RNA-binding proteins acting as exRNA carriers in biofluids, and study their roles in health and disease. This newfound knowledge is key to discover novel cell-free RNA biomarkers for early disease detection and treatment monitoring in liquid biopsies. It also lays the foundation to pioneer advanced RNA therapeutic technologies in precision medicine.
This research is done by the Mateescu Group