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Paweł Mikulski portret.JPEG

Paweł Mikulski, PhD

Group Leader

Laboratory of Immunological Epigenetics

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RESEARCH INTERESTS

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 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 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 repression of ISGs is one of the main mechanisms behind immune evasion and cancer evolution. This phenomenon opens two exciting research prospects – scientific and clinical.

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). 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 codes 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. We are aware that truly innovative research takes time (e.g. current checkpoint immunotherapies are built on decades of fundamental research), but we will capitalize on our research and entrepreneurship experience to build practical solutions to the disease.

Research interest
Members of the group
Country
Name
Surname
Email
Scientific Degree
Joanna
Bem
j.bem@imol.institute
PhD
Cita
Hanif Muflihah
c.hanifmuflihah@imol.institute
Paweł
Mikulski
p.mikulski@imol.institute
PhD

MEMBERS OF THE GROUP

PUBLICATIONS

2023

  • Tehrani S, Kogan A, Mikulski P*, Jansen L* Remembering Food and Foes: Emerging Principles of Transcriptional Memory. Cell Death & Differentiation (*co-corresponding author)

  • 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

2022

  • 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

  • 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 (*co-corresponding author, Editors’ Highlight)

2021

  • Lövkvist C, Mikulski P, Reeck S, Hartley M, Dean C, Howard M. Hybrid protein oligomer-histone modification mechanism for PRC2-based epigenetic switching and memory. eLife

  • Mikulski P*, Santos-Aberturas J. Chlamydomonas reinhardtii exhibits stress memory in the accumulation of triacylglycerols induced by nitrogen deprivation. Plant Env Interac (*corresponding author)

2020

  • Kalyanikrishna K, Mikulski P., Schubert D. Measurement of Arabidopsis thaliana nuclear size and shape. Methods Mol Biol

2019

  • Mozgova I, Mikulski P, Pecinka A, Farrona S. Epigenetic Mechanisms of Abiotic Stress Response and Memory in Plants. In: Epigenetics in Plants of Agronomic Importance: Fundamentals and Applications. Springer, Cham 2019

  • Mikulski P*, Hohenstatt ML*, Farrona S, Smaczniak C, Stahl Y, Kalyanikrishna K, Kaufmann K, Angenent GC, Schubert D. The chromatin-associated protein PWO1 interacts with plant nuclear lamin-like components to regulate nuclear size. Plant Cell (* equal contribution)

2018

  • Mikulski P*, Hohenstatt ML*, Komarynets O, Klose C, Kycia I, Jeltsch A, Farrona S, Schubert D. PWWP-DOMAIN INTERACTOR OF POLYCOMBS1 Interacts with Polycomb-Group Proteins and Histones and Regulates Arabidopsis Flowering and Development. Plant Cell (* equal contribution)

 

2017

  • Mikulski P, Komarynets O, Fachinelli F, Weber A, Schubert D. Characterization of the Polycomb-Group Mark H3K27me3 in Unicellular Algae. Front Plant Sci

2016

  • Bey T, Jamge S, Klemme S, Komar DN, Le Gall S, Mikulski P, Schmidt M, Zicola J, Berr A. Chromatin and epigenetics in all their states: Meeting report of the 1st conference on Epigenetic and Chromatin Regulation. Epigenetics

  • Bey T, Jamge S, Klemme S, Komar DN, Le Gall S, Mikulski P, Schmidt M, Zicola J, Berr A. Chromatin and epigenetics in all their states: Meeting report of the 1st conference on Epigenetic and Chromatin Regulation. Epigenetics

Publications

ABOUT GROUP LEADER

SHORT BIO

Dr Paweł Mikulski received his Msc degree from the University of Warsaw and the Institute of Biochemistry and Biophysics of the Polish Academy of Sciences. Afterwards, he did his PhD thesis in the consortium of M. Skłodowska-Curie 'EpiTraits', conducting research in 6 European institutions, e.g. Henrich Heine University Duesseldorf, University of Amsterdam, company Diagenode S.A. He completed post-doctoral stays in UK, in the groups of Prof. Dame Caroline Dean (John Innes Centre) and Prof. Lars Jansen (University of Oxford). He has been investigating epigenetic and chromatin mechanisms in the past 12 years. In his works, he showed a new link between subnuclear periphery and chromatin repression pathway, functional association of the RNA processing machinery with chromatin regulators, the structure of long non-coding RNAs and regulators of epigenetic transcriptional memory. Pawel moved back to Poland and joined IMol PAS as a Group Leader in 2023.

Group leader’s short bio

FUNDING

Group's awards:

 

2023-2026

NAWA Polish Returns Role of spatial genome architecture and related chromatin modifications in transcriptional memory within innate immunity (BPN/PPO/2022/1/00014) (PI: Paweł Mikulski)

2023 - 2026

2023-2026 NSC Sonata The discovery of multifactorial regulation at epigenetic memory of active gene expression state (2022/47/D/NZ2/01219) (PI: Paweł Mikulski)

Group leader's selected previous awards:

3 postdoctoral scholarships and grants:

 

2021 – 2022

Goodger and Schorstein Scholarship for Medical Sciences, University of Oxford, UK

2020

Biomaker grant (BBSRC-EPSRC), University of Cambridge & John Innes Centre, UK

 2019

Biomaker grant (BBSRC-EPSRC), University of Cambridge & John Innes Centre, UK

3 awards & 6 student scholarships, including:

2022

Lockey Fund travel award, University of Oxford, UK

2020

Innovate UK award as a finalist of biotech startup challenge, John Innes Centre, UK

2015

Dahlem award for a talk at Havel-Spree Colloquium, Free University Berlin, DE

2014

IE scientific management scholarship for 70% of tuition fee, IE Business School, ES

2012

Erasmus scholarship for summer internship abroad, Max Planck Institute Cologne, DE

2011

Erasmus scholarship for study semester abroad, Aarhus University, DK

2011

MOBIL research scholarship for pre-doctoral students, Aarhus University, DK

Funding
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