1. Research Background:

Throughout an animal’s lifetime, cells continuously respond to the changing environment and coordinate their behavior to maintain tissue homeostasis and function. They do so by activating signal transduction pathways that induce changes in gene expression. The rapid switching of the cellular transcriptome requires the activity of specific transcription factors coupled with precise processing of the native pre-mRNAs by the spliceosome. Aberrant gene expression caused by transcription factor and/or spliceosome dysfunction is a hallmark of age-related decline in tissue function and contributes to a wide range of diseases, including cancer, chronic inflammation, and neurodegeneration. Elucidating how transcription and pre-mRNA splicing cooperate to control cellular functions under normal and stress conditions is essential for understanding their roles in disease etiology and aging.

2. Research questions addressed by the group:

Our group studies the pleiotropic functions of the stress-inducible signaling pathways and the downstream mechanisms that govern gene expression in both physiological and pathological contexts. We study how the interplay between transcription and pre-mRNA splicing enables the generation of specific gene expression patterns required for the differentiation of functionally diverse cell types, but also allows the fine-tuning of their responses to various stress cues, providing a dynamic and adaptive ability to navigate their ever-changing environment. Our goal is to understand how co-transcriptional splicing governs essential cellular behaviors, both in physiological conditions and under stress, and how spliceosome dysregulation contributes to functional decline, aging, and disease etiology. By elucidating these processes, we aim to provide new insights into the function of fundamental biological machines, with potential implications for therapeutic intervention.

3. Possible projects:

A) Understandingthemolecularbasisofspliceosomefunctionalplasticity.

Pre-mRNA splicing catalyzed by the spliceosome is a critical step in the realization of genetic information central to development, tissue homeostasis, and healthspan in metazoans. Because most genes in higher eukaryotes contain introns and undergo alternative splicing, the “cut and join” process must be efficient and precise but also flexible to generate a specific set of transcripts on demand. Although spliceosome function is ubiquitously required in all cells, mutations or deregulation of various spliceosome components have been associated with tissue-specific pathologies and organismal aging. While considerable attention has been devoted to the functional studies of the protein components of the spliceosome our goal is to unravel the role of small nuclear RNAs and their isoforms in controlling spliceosome plasticity and the regulation of alternative splicing.

B) The role of co-transcriptional splicing in tissue maintenance and aging.

Changes in splicing factor expression and abnormal splicing patterns are recognized hallmarks of cellular senescence, aging, and age-related diseases although the functional evidence for causality remains limited. Conversely, the lifespan-enhancing effects of dietary restriction rely on tissue- specific alternative splicing (AS), and modulation of specific spliceosome components effectively extends health and lifespan in model organisms, offering potential avenues for biomedical intervention. Our goal is to understand the sex-specific requirements for spliceosome function during aging, and to determine the cellular and molecular mechanisms that render specific transcripts, cells, and tissues sensitive or resistant to splicing factor malfunctions.

C) Transcriptionalcontroloftheinnateimmunesysteminhealthanddisease.

Macrophages are vital effectors of the innate immune system and regulators of tissue homeostasis. Resident in various tissues and recruited to sites of inflammation, they provide the first line of defense against infection and injury. However, macrophages can also contribute to the pathogenesis of chronic inflammatory diseases, such as cancer, fibrosis, metabolic disorders, and allergies. Our research focuses on the mechanisms that govern macrophage development, function, and plasticity. Specifically, we investigate the transcription factor networks that coordinate the organization and dynamics of the cytoskeleton, cell membrane, and vesicle trafficking systems, processes that are crucial for macrophage motility and their interactions with healthy, injured, or diseased tissues, as well as with pathogens. Our goal is to understand how transcriptional regulation coordinates lipid metabolism with cellular mechanics to sustain macrophage functional plasticity and immune responsiveness. We investigate how these networks are rewired in response to immune stimulation, aging, and disease.

D) Immune cell-nicheinteractions.

Immune cell differentiation and function are tightly linked to specialized compartments known as niches. Hematopoietic and tissue-specific niches provide microenvironments that support self- renewal, progenitor maintenance, and immune cell differentiation in response to tissue and organismal needs. Crosstalk within these niches involves biochemical and mechanical signaling, including secreted factors, cell-matrix interactions, and cell-cell communication. Disruption of niche integrity can impair tissue function and contribute to disease. Our goal is to define the structural relationships and regulatory mechanisms governing immune cell-niche interactions and to elucidate how these contribute to immune and tissue homeostasis, and pathology.

4. Applied Methods and model organisms:

Our group uses Drosophila and mouse models, insect and mammalian cultured cells. We combine functional genetics and genome engineering (CRISPR/Cas9) with a wide range of cell and molecular biology techniques, advanced microscopy and live imaging, biochemistry, genomic and proteomic approaches.

5. Desirable skills and qualifications:

We seek curious, motivated, and reliable candidates with a strong theoretical background in genetics, molecular and cell biology, and extensive hands-on wet lab experience. Excellent communication, problem-solving and analytical skills, fluency in spoken and written English, and basic knowledge of bioinformatics are desired. Experience with Drosophila or mouse models is an advantage.

6. References:

1. Burgmer S, Meyer Zu Altenschildesche FL, Gyenis A, Lee HJ, Vilchez D, Giavalisco P, Fichant A, Uhlirova M & Storelli G. (2025) Endosymbiont control through non-canonical immune signaling and gut metabolic remodeling, Cell Reports, 44, 115811, doi: 10.1016/j.celrep.2025.115811.
2. Stanković D, Tain LS & UhlirovaM.(2024) Xrp1 governs the stress response program to spliceosome dysfunction, Nucleic Acids Research, 52, 2093–2111., gkae055, doi: 10.1093/nar/gkae055.
3. Floc'hlay S, Balaji R, Stankovic D, Christiaens VM, Bravo Gonzalez-Blas C, De Winter S, Hulselmans GJ, De Waegeneer M, Quan X, Koldere D, Atkins M, Halder G, Uhlirova M, Classen A & Aerts S. (2023) Shared enhancer gene regulatory networks between wound and oncogenic programs, Elife. 12, e81173, doi: 10.7554/eLife.81173
4. Külshammer E, Kilinc M, Csordás G, Bresser T, Nolte H, UhlirovaM.(2022) The mechanosensor Filamin A/Cheerio promotes tumorigenesis via specific interactions with components of the cell cortex. FEBS Journal, 289, 4497-4517. doi: 10.1111/febs.16408
5. Erkelenz S, Stankovic D, Mundorf J, Bresser T, Claudius A-K, Boehm V, Gehring NH, UhlirovaM. (2021) Ecd promotes U5 snRNP maturation and Prp8 stability. Nucleic Acids Research, 49, 1688-1707. doi.org/10.1093/nar/gkaa1274
6. Csordás G, Grawe F, UhlirovaM. (2020) Eater cooperates with Multiplexin to drive the formation of hematopoietic compartments. eLife 9: e5729. doi: 10.7554/eLife.57297.
7. Stankovic D, Claudius A, Schertel T, Bresser T, UhlirovaM. (2020). Drosophila model to study Retinitis pigmentosa pathology associated with mutations in the core splicing factor Prp8. Disease Models & Mechanisms 13: dmm043174. doi: 10.1242/dmm.043174
8. Mundorf J, Donohoe CD, McClure CD, Southall TD, UhlirovaM. (2019) Ets21c governs tissue renewal, stress tolerance, and aging in the Drosophila intestine. Cell Reports, 27: 3019- 3033.e5. doi: 10.1016/j.celrep.2019.05.025.
9. Donohoe CD, Csordás G, Correia A, Jindra M, Klein C, Habermann B, UhlirovaM. (2018) Atf3 links loss of epithelial polarity to defects in cell differentiation and cytoarchitecture. PLOS Genetics 14, e1007241, doi: 10.1371/journal.pgen.1007241