Research profile

Current cancer immunotherapies are effective only in ~40-60% of the cases. One of the main reasons behind such inefficiency is the escape of cancer cells from host immune surveillance (immune evasion) by epigenetic & chromatin de-regulation of immune response genes. The aim of the Laboratory is to decipher the mechanisms of repression and activation of immune response genes in cancer cells and use them to develop new types of immunotherapies.

Our primary focus is the regulation of immune response loci such as Interferon-stimulated genes (ISGs). ISGs are abundant (~10% of human coding genome) and tightly regulated immune response genes whose expression is activated by cytokines – interferons. ISGs are crucial for controlling inflammation and signalling between infected or cancer-transformed cells and host immune system. ISGs’ expression triggers pathogen clearance and recognition of tumours by immune system. Due to their crucial role in limiting cancer proliferation, epigenetic de-regulation of ISGs is one of the main mechanisms behind immune evasion and cancer evolution. This phenomenon opens two exciting research prospects – scientific and clinical.

More infromation: https://sites.google.com/view/mikulski-lab

Current research activities

On the scientific side, we found out that activation and repression of ISGs is regulated by a complex network of factors. Notably, changes in their expression state are associated with dynamic remodelling of chromatin (i.e., differential balance between active and repressive chromatin modifications), genome architecture (i.e., loops between enhancer/silencers and promoters) and alternative transcription (i.e., regulated expression from multiple transcriptional start sites (TSSs) ). Furthermore, we revealed that selected ISGs are subjects of transcriptional memory – their activation can be memorized post-stimulus even in continuously proliferating cells and allow faster/higher activation upon stimulus re-challenge. How all these factors cooperate in gene regulation, what encodes transcriptional memory and what underlies switches between active-repressive expression state remains unknown. The Lab aims to address these knowledge gaps and use ISGs as a paradigm for regulation of gene expression and epigenetic inheritance of active chromatin state – two aspects of molecular biology with incomplete understanding and fundamental importance.

On the clinical side, ISG-mediated immune evasion, despite widespread occurrence, remains largely unaddressed by current clinical cancer treatments. Current immunotherapies largely do not directly modulate ISGs’ expression in cancer cells and do not restore ISGs-dependent immune surveillance. Through work on fundamental principles behind ISG regulation, our applied long-term aim is the development of first-in-class immunotherapy centered at modulation of ISGs’ expression. Acknowledging that truly innovative research takes time (e.g. current checkpoint immunotherapies are built on decades of fundamental research), we are employing our mechanistic findings to build practical solutions to the disease.

Selected publications

Mikulski P*, Tehrani S, Kogan A, Abdul-Zani I, Shell E, Ryan B, Jansen L*. Heritable maintenance of chromatin modifications confers transcriptional memory of interferon-γ signaling. Nature Struc & Mol Bio 2025 (*corresponding authors) https://doi.org/10.1038/s41594-025-01522-8

Tehrani S, Kogan A, Mikulski P*, Jansen L* Remembering Food and Foes: Emerging Principles of Transcriptional Memory. Cell Death & Differentiation 2023 (*co-corresponding author) https://doi.org/10.1038/s41418-023-01200-6

Tehrani S, Mikulski P, Abdul-Zani I, Mata J, Siwek W, Jansen L STAT1 is required to establish but not maintain IFNγ-induced transcriptional memory. EMBO J 2023 https://doi.org/10.15252/embj.2022112259

Yang M, Zhu P, Cheema J, Bloomer R, Mikulski P, Liu Q, Zhang Y, Ding Y, Dean C In vivo single-molecule analysis reveals COOLAIR RNA structural diversity. Nature 2022 https://doi.org/10.1038/s41586-022-05135-9

Mikulski P*, Wolff, P., Lu, T, Nielsen M, Echevarria E, Zhu D, Questa J, Saalbach G, Martins C, Dean C*. VAL1 as an assembly platform co-ordinating co-transcriptional repression and chromatin regulation at Arabidopsis FLC. Nature Communications 2022 (*co-corresponding author, Editors’ Highlight) https://doi.org/10.1038/s41467-022-32897-7