The overarching topic of our research is genome regulation by tumor suppressors and oncoproteins. Three interconnected research topics, namely genome regulation by the tumor suppressor p53, gene regulation during the cell cycle, and growth control by the transcription factor RFX7, contribute to a better understanding of genome regulatory mechanisms and their role in cancer development and therapy. By investigating these topics, we aim to uncover shared regulatory pathways across a range of cell types, advancing our understanding of genome regulation in various biological contexts.
Our research sits at the crossroads of biochemistry, molecular genetics, and bioinformatics, seeking to identify the molecular mechanisms that act as critical regulatory barriers in cellular processes, including tumor progression. We integrate experimental work with human cell lines (from both tumor and normal cells) and cutting-edge omics technologies, bioinformatically linking this data with public resources to build detailed models of gene regulatory networks. This enables us to uncover how these networks control cell fate decisions central to tumor development.
A key focus of our work is identifying the mechanisms that govern gene expression and the resulting gene signatures. These signatures are becoming invaluable tools in both research and clinical applications, offering a robust, accessible means of monitoring signaling pathway activity. This research not only enhances our understanding of the molecular foundations of biology and disease but also holds promise for developing new diagnostic tools and therapies tailored to the specific regulatory networks driving individual tumors.
Genome regulation by the tumor suppressor p53
The transcription factor p53 has a central role in preventing tumor progression and is among the most extensively studied genes in cancer research. It controls cell growth and programmed cell death (apoptosis) by regulating a wide range of target genes. Cancer cells, however, often find ways to bypass the tumor-suppressing function of p53, either through mutations in TP53, the gene that encodes p53, or by disrupting the broader p53 signaling network.
Despite extensive research, we still lack a complete understanding of the molecular mechanisms behind p53-dependent gene regulation – a gap that limits our overall insight into tumor suppression. How p53 regulates many of its target genes, which co-factors are required for this regulation, and the impact of these processes on the life cycle of normal versus cancerous cells remain unclear. Our research aims to uncover the pathways that mediate gene regulation by p53 and to explore whether targeting these pathways could open new avenues for cancer treatment.
Current external funding: DFG projects Fi 1993/6-1 and FI 1993/7-1
Key research publications
- Wiechens E, Vigliotti1 F, Siniuk1 K, Schwarz R, Schwab K, Riege K, van Bömmel A, Görlich I, Bens M, Sahm A, Groth M, Sammons MA, Loewer A, Hoffmann# S, Fischer# M (2025) Gene regulation by convergent promoters. Nat. Genet. 57 (1): 206–217
- Fischer# M, Riege K, Hoffmann S (2023) The landscape of human p53-regulated long non-coding RNAs reveals critical host gene co-regulation. Mol. Oncol.
- Coronel L, Riege K, Schwab K, Förste S, Häckes D, Semerau L, Bernhart SH, Siebert R, Hoffmann# S, Fischer# M (2021) Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress. Nucl. Acids Res. 49 (13): 7437-7456
- Riege K, Kretzmer H, Sahm A, McDade SS, Hoffmann S, Fischer# M (2020) Dissecting the DNA binding landscape and gene regulatory network of p63 and p53. eLife 9: e63266
- Fischer# M (2019) Conservation and divergence of the p53 gene regulatory network between mice and humans. Oncogene 38 (21): 4095-4109
- Fischer# M, Grossmann P, Padi M, DeCaprio JA (2016) Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks. Nucl. Acids Res. 44 (13): 6070-6086
- Fischer M, Quaas M, Steiner L, Engeland# K (2016) The p53-p21-DREAM-CDE/CHR pathway regulates G2/M cell cycle genes. Nucl. Acids Res. 44 (1): 164-174
- Fischer# M, Steiner L, Engeland# K (2014) The transcription factor p53: Not a repressor, solely an activator. Cell Cycle 13 (19): 3037-3058
Growth suppression by the transcription factor RFX7
The transcription factor regulatory factor X 7 (RFX7) has emerged as a regulator in various diseases, especially blood cancers such as Burkitt’s lymphoma and chronic lymphocitic leukemia. Evidence from animal models suggests roles for RFX7 in neural development, immune cell maturation, metabolic regulation, and tumor suppression. Our reserach uncovered that RFX7 directly controls several known tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1 and that its activity is positioned as a crucial link in activating these tumor suppressors in response to p53 and cellular stress.
Our findings also show that expression of RFX7 target genes is associated with cell differentiation and better prognoses in multiple cancer types. Notably, RFX7 enhances cell sensitivity to the chemotherapy drug doxorubicin by promoting apoptosis and is necessary for p53 to inhibit key survival pathways involving AKT and mTOR. Together, these findings highlight RFX7 as a central regulator of cell growth and fate decisions and a crucial component within the p53 transcriptional network. Our ongoing research aims to further chracterize the functional roles of RFX7 as a novel tumor suppressor, with promising implications for new cancer treatment strategies.
Current external funding: Carl Zeiss Foundation and SPARK@FLI
Key research publications
- Schwab K, Riege K, Coronel L, Stanko C, Förste S, Hoffmann# S, Fischer# M (2024) p53 target ANKRA2 cooperates with RFX7 to regulate tumor suppressor genes. Cell Death Discov. 10: 376
- Schwab K, Coronel L, Riege K, Sacramento EK, Rahnis N, Häckes D, Cirri E, Groth M, Hoffmann S, Fischer# M (2023) Multi-omics analysis identifies RFX7 targets involved in tumor suppression and neuronal processes. Cell Death Discov. 9: 80
- Coronel1 L, Häckes1 D, Schwab1 K, Riege K, Hoffmann# S, Fischer# M (2022) p53-mediated AKT and mTOR inhibition requires RFX7 and DDIT4 and depends on nutrient abundance. Oncogene 41 (7): 1063-1069
- Coronel L, Riege K, Schwab K, Förste S, Häckes D, Semerau L, Bernhart SH, Siebert R, Hoffmann# S, Fischer# M (2021) Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress. Nucl. Acids Res. 49 (13): 7437-7456
Coordinated gene expression during the cell cycle
Precise timing in cell cycle gene expression is crucial for controlling cell proliferation. When this timing is dysregulated, it can drive cancer formation and lead to defects in cell differentiation and development. To enter and progress through the S phase, cells must express genes that encode proteins essential for DNA replication. Similarly, a different set of genes is needed to progress through mitosis and cytokinesis. The regulation of these distinct groups of cell cycle genes is controlled by the RB pocket protein family, the E2F transcription factor family, and MuvB complexes (such as the DREAM complex), which coordinate with additional transcriptional regulators like B-MYB and FOXM1. Together, these transcription factors drive the expression of genes that peak in S phase (G1/S) and mitosis (G2/M).
The tumor suppressor p53 can halt cell proliferation by modulating these transcription factors. Our research focuses on uncovering mechanisms that limit cell cycle gene expression when it is unnecessary, such as during cellular quiescence, and mechanisms that drive the precise timing of gene expression required for normal cell cycle progression. By understanding these regulatory pathways, we aim to provide insights that could lead to improved treatment strategies for cancers driven by cell cycle dysregulation
Key publications
- Fischer# M, Schade AE, Branigan TB, Müller GA, DeCaprio# JA (2022) Coordinating gene expression during the cell cycle. Trends Biochem. Sci. 47 (12): 1009-1022
- Fischer1,# M, Müller1,# GA (2017) Cell cycle transcription control: DREAM/MuvB and RB-E2F complexes. Crit. Rev. Biochem. Mol. Biol. 52 (6): 638-662
- Fischer# M, Uxa S, Stanko C, Magin TM, Engeland# K (2017) The human papillomavirus oncoprotein E7 abrogates the p53-p21-DREAM pathway. Sci. Rep. 7 (1): 2603
- Fischer# M, Grossmann P, Padi M, DeCaprio JA (2016) Integration of TP53, DREAM, MMB-FOXM1 and RB-E2F target gene analyses identifies cell cycle gene regulatory networks. Nucl. Acids Res. 44 (13): 6070-6086
- Fischer M, Quaas M, Steiner L, Engeland# K (2016) The p53-p21-DREAM-CDE/CHR pathway regulates G2/M cell cycle genes. Nucl. Acids Res. 44 (1): 164-174
- Fischer M, Quaas M, Wintsche A, Müller GA, Engeland# K (2014) Polo-like kinase 4 transcription is activated via CRE and NRF1 elements, repressed by DREAM through CDE/CHR sites and deregulated by HPV E7 protein. Nucl. Acids Res. 42 (1): 163-180
Current and Previous Funders
We are very grateful for the support we have received from various funding organizations.
