Research Area: Stress response Mechanisms of tissue-related and interorgan Communication in Ageing and age-associated diseases
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 a precise processing of the native pre-mRNAs by the spliceosome. The aberrant gene expression as a consequence of 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 factors and pre-mRNA splicing control distinct cellular functions to maintain tissue homeostasis 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 elucidates the pleiotropic functions of the stress-inducible signaling pathways and downstream mechanisms governing gene expression in the physiological and pathological contexts. We study how diverse stress signals impact transcription factor and spliceosome activity and splicing accuracy. We focus on mechanisms that collaborate with the pre-mRNA processing machinery to generate cell type- and life stage-specific splicing patterns. We use genetic and molecular approaches to identify the stress-inducible and DNA damage-related genetic networks that respond to spliceosome deregulation and decipher how they contribute to loss of tissue homeostasis, premature aging, and disease phenotypes.
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 the vast majority of 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 formation and functions of the multinucleated giant macrophages in health and chronic inflammatory state.
Macrophages are vital effectors of the innate immune system and important modulators of adaptive immunity. 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. Intriguingly, macrophages can differentiate into multinucleated giant cells (MGCs) containing dozens of nuclei through acytokinetic division and/or cell-cell fusion. The physiological form of MGCs is represented by the bone resorbing osteoclasts, which play a vital role in bone homeostasis and remodeling. However, MGCs are also a shared feature of granulomatous inflammatory disorders, including tuberculosis, atherosclerosis and a foreign body reaction to amyloid fibers or implants. Our primary goal is to identify the cellular machineries and molecular mechanisms required for the formation and function of the MGCs. In particular, 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 the process of cell-cell fusion and MGC behavior.
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 (RNA-seq, DamID, ChIP-seq) 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 previous hands-on wet lab experience. Good 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.
- 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
- 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.
- 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.
- 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
- 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.
- 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.