1. Research Background:

Throughout an animal’s lifetime, cells continuously react to the changing environment and coordinate their behaviors to maintain tissue homeostasis and function. They do so by activating signal transduction pathways that evoke changes in gene expression. The rapid switch of cellular transcriptome requires the activity of specific transcription factors coupled with precise processing of the native pre-mRNAs by the spliceosome. The aberrant gene expression caused by transcription factor and/or spliceosome malfunction hallmarks age-associated decline of tissue function and contributes to a wide range of diseases, including cancer, chronic inflammatory disorders, and neurodegeneration. Unraveling 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 addresses by the group:

Our group investigates the pleiotropic functions of the stress-inducible signaling pathways and downstream mechanisms orchestrating gene expression in the context of epithelial tissues and innate immune cells. We study how diverse stress signals modulate transcription factor and spliceosome activities during development and physiology and how malfunction of transcription and splicing machinery affect epithelial and immune cell behaviors and the interactions between the two systems during aging and disease.

3. Possible projects:

The projects pursued in our group are tailored to fit our continuous efforts to elucidate the molecular mechanisms that link stress signaling to the regulation of gene expression and the maintenance of genome integrity during development, aging, and diseases.

• A) To investigate the mechanisms underlying the functional plasticity of the spliceosome and the molecular link between pre-mRNA splicing and the maintenance of the transcriptome and genome integrity.
  Pre-mRNA splicing catalyzed by the spliceosome represents a crucial step in the realization of genetic information pivotal to development, tissue homeostasis, and healthspan in metazoans. Given that 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 required ubiquitously in all cells, mutations or deregulation of different spliceosome components have been associated with tissue-specific pathologies and organismal aging. Moreover, the tight coupling between pre-mRNA splicing and transcription highlighted the role of splicing factors as gatekeepers of genome stability. In our lab, we study how spliceosome assembles under physiological and stress conditions and what dictates spliceosome composition and its functional plasticity. We aim to determine the cellular and molecular mechanisms rendering specific transcripts, cells, and tissues sensitive or resistant to splicing factor malfunctions and the genetic network linking pre-mRNA splicing to the maintenance of transcriptome and genome integrity. Moreover, we decipher how cells affected by spliceosome malfunction communicate the defects to their neighbors within the same tissue and systemically to the distant organs.
• B) To understand the mechanisms governing the development and functions of the cellular branch of the innate immune system in health and disease.
  Macrophages are vital effectors of the innate immune system and regulators of tissue homeostasis. Residing in different tissues and recruited to sites of inflammation, they provide the first line of defense against infection and injury by removing invading pathogens, cellular debris, and apoptotic cells via phagocytosis. Macrophages can, however, actively contribute to the pathogenesis of chronic inflammatory disorders, including cancer, fibrosis, metabolic disorders, and sepsis. We study the cellular machinery and molecular mechanisms required for the formation and function of macrophages and their plasticity. We focus on the transcription factor network that governs the organization and dynamics of the cellular cytoskeleton, the cell membrane, and the vesicle trafficking apparatus, which coordinated activities are required for macrophage motility and interactions with healthy, wounded, or diseased tissue and pathogens.

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. 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
2. Külshammer E, Kilinc M, Csordás G, Bresser T, Nolte H, Uhlirova M. (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
3. Erkelenz S, Stankovic D, Mundorf J, Bresser T, Claudius A-K, Boehm V, Gehring NH, Uhlirova M. (2021) Ecd promotes U5 snRNP maturation and Prp8 stability. Nucleic Acids Research, 49, 1688-1707. doi.org/10.1093/nar/gkaa1274
4. Csordás G, Grawe F, Uhlirova M. (2020) Eater cooperates with Multiplexin to drive the formation of hematopoietic compartments. eLife 9: e5729. doi: 10.7554/eLife.57297.
5. Stankovic D, Claudius A, Schertel T, Bresser T, Uhlirova M. (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
6. Mundorf J, Donohoe CD, McClure CD, Southall TD, Uhlirova M. (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.
7. Cosolo A, Jaiswal J, Csordás G, Grass I, Uhlirova M, Classen A. (2019) JNK-dependent cell cycle stalling in G2 promotes survival and senescence-like phenotypes in tissue stress. eLife, 8: e41036. doi: 10.7554/eLife.41036.
8. Donohoe CD, Csordás G, Correia A, Jindra M, Klein C, Habermann B, Uhlirova M. (2018) Atf3 links loss of epithelial polarity to defects in cell differentiation and cytoarchitecture. PLOS Genetics 14, e1007241, doi: 10.1371/journal.pgen.1007241
9. Külshammer E, Mundorf J, Kilinc M, Frommolt P, Wagle P, Uhlirova M. (2015) Interplay among transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy. Disease Models & Mechanisms 8, 1279–1293, doi: 10.1242/dmm.020719.
10. Claudius A, Romani P, Lamkemeyer T, Jindra M, Uhlirova M. (2014) Unexpected Role of the Steroid-Deficiency Protein Ecdysoneless in Pre-mRNA Splicing. PLOS Genetics 10, e1004287, doi: 10.1371/journal.pgen.1004287.