INTERROGATING ENHANCER-PROMOTER INTERACTIONS

The complex regulation of gene expression involves dynamic interplays among cis-acting regulatory components, such as promoters, enhancers, and silencers. The mechanisms underlying the communication between these elements to regulate cellular function and development are still not completely understood.

In this project, we aim to understand how interactions between enhancer and promoter sequences, as well as their relative linear positions, influence gene expression. To investigate this, the student will generate a ‘landing pad’ within the mouse embryonic stem cell genome to integrate enhancers and analyze their gene expression patterns.

During this project, the student will gain hands-on experience in culturing and manipulating mouse embryonic stem cells, genome editing using CRISPR-Cas9 technology, and basic molecular biology techniques (PCR, cloning etc) to uncover the dynamics of enhancer-promoter communication.

The student will join a highly motivated and international research team. They will regularly interact with and learn from experienced mentors and peers through weekly lab meetings, journal clubs, and collaborative troubleshooting sessions. The student will be encouraged to actively contribute ideas, fostering a supportive and intellectually stimulating environment.

ROLE OF HETEROCHROMATIN SPATIAL ORGANIZATION IN THE RESPONSE TO ENVIRONMENTAL STRESS

In our lab, we are interested in understanding how environmental perturbations affect chromatin organization with consequences for organismal health.

The sequestration of heterochromatin, the silenced portion of the genome, at the nuclear periphery is conserved from yeast to man, and altered in cancer, laminopathies, and aging. However, the function of 3D heterochromatin organization remains largely unknown due to the inability to perturb it while leaving other nuclear processes unaltered.

For this summer internship program, the student joining our group will use C. elegans, the only multicellular organism where a protein acting as a perinuclear anchor for heterochromatin was described to date, to investigate the role of heterochromatin spatial positioning. Specifically, he/she will assist a PhD student in testing our hypothesis that 3D genome organization plays a critical role in the response to unscheduled transcriptional stimuli induced by environmental stress.

During the internship, the student will actively participate in stress survival assays and live-imaging experiments to evaluate the effects of stress exposure in both wild-type and chromatin mutant strains. Additionally, the internship will provide training in essential C. elegans laboratory techniques, including maintaining and synchronizing worm populations and performing crosses.

Group Leader: Dr. Daphne Cabianca

Institute: Institute of Functional Epigenetics

UNDERSTANDING LEUKEMIA AND PRE-LEUKEMIC CONDITIONS THROUGH MULTI-MODAL SINGLE-CELL INTEGRATIVE ANALYSIS 

Recent advancements in single-cell technologies and computational approaches have enhanced the ability to dissect the molecular mechanisms underlying leukemia and pre-leukemic conditions, at unprecedented resolution.

This project focuses on applying state-of-the-art computational pipelines to analyze multi-modal single-cell data of human blood from both diseased and healthy donors. As our summer intern, you will perform scRNA-seq and scATAC-seq data analysis, covering data preprocessing, cell cluster annotation, differential expression analysis, gene set enrichment analysis, and cell-to-cell communication analysis. You will also explore chromatin accessibility, perform motif accessibility analysis, and infer gene regulatory networks.

You will learn and implement the best practices for single-cell analysis as described by Heumos et al., ensuring reproducible workflows. Tools such as Scanpy, scVI tools, ArchR, and CellChat will be utilized to process and integrate datasets.

IMPORTANT: Requirements

• Working knowledge of Python (MANDATORY)
• Familiarity with R (recommended)
• Experience with single-cell data analysis (recommended)

BEFORE APPLYING FOR THIS PROJECT, PLEASE READ HERE ITS DETAILS.

Group Leader: Prof. Carsten Marr

Institute: Institute of Artifical Intelligence for Health

CONSEQUENCE OF MITOCHONDRIAL DNA COPY NUMBER CHANGES ON CELL FUNCTION

Mitochondria of almost all eukaryotic cells contain their own genome, the mitochondrial DNA (mtDNA), which encodes for several proteins that are essential for oxidative phosphorylation. Typically, cells contain multiple copies of mtDNA, which are distributed throughout the mitochondrial network. mtDNA copy number is regulated according to external and internal cues, including cell type and nutrient availability. Accordingly, misregulation of mtDNA copy number is associated with severe diseases and aging. However, the mechanisms through which mtDNA copy number affects mitochondrial and cell function are surprisingly poorly understood.

Recently, we identified cell-size dependent regulation as a key mechanism controlling mtDNA copy number in budding yeast (Seel et al., 2023). We found that mtDNA copy number is set by the abundance of key limiting nuclear encoded factors, including the mitochondrial DNA polymerase Mip1, and the packaging factor Abf2. Genetic manipulation of the concentration of these factors leads to a proportional increase or decrease of mtDNA copy number, providing a unique opportunity to investigate the consequence of such mtDNA copy number changes on cell function.

In this project, you will use this powerful model system and a combination of yeast genetics, molecular biology and quantitative live-cell imaging to investigate how mtDNA copy number affects mitochondrial organization and function, how it affects expression of mitochondrial encoded genes, and how cells cope with these changes.

TRANSCRIPTIONAL MEMORY AT THE SINGLE-CELL LEVEL

Upon repetitive exposure to the same stimulus certain genes can adapt their subsequent responses. This so-called transcriptional memory is important for the adaptation of gene expression during repetitive environmental stresses. Transcriptional memory could have important consequences on cell survival and for disease progression and innate immunity in humans. Thus, a comprehensive understanding of transcriptional memory is important from fundamental perspective, as well as for potentially developing better treatment for associated diseases.

The project for the summer student will focus on understanding of how long transcriptional memory at the single-cell can be maintained. More specifically how long can single cells “remember” that they experienced a similar stimulus before, and which perturbation might “erase” this memory. The project will be performed together with an experienced supervisor.

This internship includes the possibility to be part of a very dynamic and international team, learn state of the art technologies (single-cell imaging, single-cell microfluidics, neural network-based data analysis, etc.) and get novel inside into transcriptional memory and fundamental questions behind it. Join us to harness new and exciting knowledge to move forward fundamental science and potentially contribute to a healthier society in a rapidly changing world!

Group Leader: Prof. Robert Schneider

Institute: Institute of Functional Epigenetics

EXPLORING THE GENOMIC AND SPATIAL DYNAMICS OF FATE DECISION IN OLFACTORY SENSORY NEURONS

Odorant detection is a complex biological process involving coordination across tissues and scales[1]. Olfactory sensory neurons (OSNs) achieve this by expressing only one allele of an olfactory receptor (OR) gene from a repertoire of over one thousand options[2]. While OR choice is stochastic, it is influenced by the spatial location of the neuron within the olfactory epithelium, which is divided into distinct zones with unique OR compositions[3, 4, 5]. Additionally, OR genes are organized into clusters distributed across almost all chromosomes, creating a complex genomic architecture[2, 6].

This project aims to investigate the relationship between the genomic organization of OR genes and the macroscopic spatial organization of their expression patterns. The student will analyze single-cell and spatial transcriptomic data to determine how specific OR gene clusters are differentially expressed across zones in the olfactory epithelium.

During this internship, the student will gain hands-on experience in machine learning and programming, learning to process, analyze, and visualize complex transcriptomic datasets. As part of a dynamic, international research team working at the forefront of computational biology, the student will develop valuable technical and research skills while contributing to a fundamental question in epigenetics.

[1] Monahan, K. & Lomvardas, S. Monoallelic Expression of Olfactory Receptors. Annual Review of Cell and Developmental Biology 31:721-740, (2015).

[2] Yusuf, N. & Monahan, K. Epigenetic programming of stochastic olfactory receptor choice. genesis 62, e23593 (2024).

[3] Ruiz Tejada Segura, M. L. et al. A 3D transcriptomics atlas of the mouse nose sheds light on the anatomical logic of smell. Cell Reports 38, 110547 (2022).

[4] Bashkirova, E. V. et al. Opposing, spatially-determined epigenetic forces impose restrictions on stochastic olfactory receptor choice. eLife 12, RP87445 (2023)

[5] Tan, L. & Xie, X. S. A Near-Complete Spatial Map of Olfactory Receptors in the Mouse Main Olfactory Epithelium. Chemical Senses 43, 427–432 (2018).

[6] Pourmorady, A. D. et al. RNA-mediated symmetry breaking enables singular olfactory receptor choice. Nature 625, 181–188 (2024).

REGULATION OF GENE EXPRESSION IN PLURIPOTENT AND TOTIPOTENT CELLS

The project proposed aims at delving into the epigenetic mechanisms that allow early embryonic cells to acquire their identity and plasticity. Cellular plasticity is the capacity of a cell to give rise to different cell types upon differentiation.

In particular, the student will work with cell culture models to identify the function of cis-regulatory regions and non-coding elements in the genome.  They will implement cell biology and molecular biology approaches to understand the function and structure of genomic elements to regulate gene expression in pluripotent and totipotent cells. 

The student will be able to grow and culture embryonic stem cells and manipulate the cells with transfection and/or CrisprCas9-based epigenetic engineering and ectopic expression of chromatin modifiers.

Overall, the project proposed aims to uncover the epigenetic mechanisms behind the establishment of totipotency and to provide insights into the origin of first pluripotent stem cells to form.

Group Leader: Prof. Maria-Elena Torres-Padilla

Institute: Institute for Epigenetics and Stem Cells