Lea Sistonen

Turku Centre for Biotechnology

Human gamma-herpesviruses, Kaposi's sarcoma herpesvirus (KSHV) and Epstein-Barr virus (EBV) are causally associated to a wide range of cancers. While the default infection program for these viruses is latent, sporadic lytic reactivation supports virus dissemination and oncogenesis. Despite its relevance, the repertoire of host factors governing the...

Heat shock factor 2 (HSF2) is a versatile transcription factor that regulates gene expression under stress conditions, during development, and in disease. Despite recent advances in characterizing HSF2‐dependent target genes, little is known about the protein networks associated with this transcription factor. In this study, we performed co‐immunop...

Transcriptional reprogramming drives differentiation and coordinates cellular responses. While mRNA expression in distinct cell types has been extensively analyzed, the mechanisms that control RNA synthesis upon lineage specifications remain unclear. Here, we induce erythroid differentiation in human cells, track transcription and its regulation at...

Phenotypic plasticity is a hallmark of breast carcinogenesis that facilitates the acquisition of invasive properties via epithelial-mesenchymal transition (EMT). Transforming growth factor-beta (TGF-β), a key EMT-inducing cytokine, drives pro-metastatic gene programs through downstream transcription factors. Among mammalian stress-protective transc...

Heat shock factors (HSFs) are the main transcriptional regulators of the evolutionarily conserved heat shock response. Beyond cell stress, several studies have demonstrated that HSFs also contribute to a vast variety of human pathologies, ranging from metabolic diseases to cancer and neurodegeneration. Despite their evident role in mitigating cellu...

Preserving and regulating cellular homeostasis in the light of changing environmental conditions or developmental processes is of pivotal importance for single cellular and multicellular organisms alike. To counteract an imbalance in cellular homeostasis transcriptional programs evolved, called the heat shock response, unfolded protein response, an...

Extracellular vesicles (EVs) are important mediators of intercellular communication involved in local and long‐range signalling of cancer metastasis. The onset of invasion is the key step of the metastatic cascade, but the secretion of EVs has remained unexplored at that stage due to technical challenges. In this study, we present a platform to tra...

The Second International Symposium on Cellular and Organismal Stress Responses took place virtually on September 8–9, 2022. This meeting was supported by the Cell Stress Society International (CSSI) and organized by Patricija Van Oosten-Hawle and Andrew Truman (University of North Carolina at Charlotte, USA) and Mehdi Mollapour (SUNY Upstate Medica...

Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize t...

Reprogramming of transcription is critical for the survival under cellular stress. Heat shock has provided an excellent model to investigate nascent transcription in stressed cells, but the molecular mechanisms orchestrating RNA synthesis during other types of stress are unknown. We utilized PRO-seq and ChIP-seq to study how Heat Shock Factors, HSF...

Talin 1 (TLN1) is best known for its role at focal adhesions, where it activates β-integrin receptors and transmits mechanical stimuli to the actin cytoskeleton. Interestingly, the localization of TLN1 is not restricted to the focal adhesions, but its function in other cellular compartments remains poorly understood. By utilizing both biochemical a...

Nascent RNA-sequencing tracks transcription at nucleotide resolution. The genomic distribution of engaged transcription complexes, in turn, uncovers functional genomic regions. Here, we provide analytical steps to (1) identify transcribed regulatory elements de novo genome-wide, (2) quantify engaged transcription complexes at enhancers, promoter-pr...

Reprogramming of transcription is critical for the survival under cellular stress. Heat shock has provided an excellent model to investigate nascent transcription in stressed cells, but the molecular mechanisms orchestrating RNA synthesis during other types of stress are unknown. We utilized PRO-seq and ChIP-seq to study how Heat Shock Factors, HSF...

The heat‐shock factors (HSFs) belong to an evolutionary conserved family of transcription factors that were discovered already over 30 years ago. The HSFs have been shown to a have a broad repertoire of target genes, and they also have crucial functions during normal development. Importantly, HSFs have been linked to several disease states, such as...

SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO ma...

Nascent RNA-sequencing tracks transcription at nucleotide resolution. The genomic distribution of engaged transcription complexes, in turn, uncovers functional genomic regions. Here, we provide data-analytical steps to 1) identify transcribed regulatory elements de novo genome-wide, 2) quantify engaged transcription complexes at enhancers, promoter...

The Federation of American Societies for Experimental Biology (FASEB) virtual Catalyst Conferences are meetings geared to establish a scientific community around an emerging scientific topic in the field. The first FASEB virtual Catalyst Conference on Extracellular and Organismal Proteostasis in Health and Disease was held on February 3-4, 2021, or...

Heat shock instantly reprograms transcription. Whether gene and enhancer transcription fully recover from stress and whether stress establishes a memory by provoking transcription regulation that persists through mitosis remained unknown. Here, we measured nascent transcription and chromatin accessibility in unconditioned cells and in the daughters...

Extracellular vesicles (EVs) loaded with biomolecules are important in intercellular communication and mediate local and long-range signals in cancer metastasis. However, it is currently unknown how the development of the primary tumor and onset of invasion affect the secretion and characteristics of EVs. In this study, we developed an EV productio...

Malignant transformation is accompanied by alterations in the key cellular pathways that regulate development, metabolism, proliferation and motility as well as stress resilience. The members of the transcription factor family, called heat shock factors (HSFs), have been shown to play important roles in all of these biological processes, and in the...

Maintenance of protein homeostasis, through inducible expression of molecular chaperones, is essential for cell survival under protein-damaging conditions. The expression and DNA-binding activity of heat shock factor 2 (HSF2), a member of the heat shock transcription factor family, increase upon exposure to prolonged proteotoxicity. Nevertheless, t...

Cellular stress triggers reprogramming of transcription, which is required for the maintenance of homeostasis under adverse growth conditions. Stress-induced changes in transcription include induction of cyto-protective genes and repression of genes related to the regulation of the cell cycle, transcription and metabolism. Induction of transcriptio...

The extracellular molecular chaperone heat shock protein 90 (eHSP90) stabilizes protease client the matrix metalloproteinase 2 (MMP2), leading to tumor cell invasion. Although co-chaperones are critical modulators of intracellular HSP90:client function, how the eHSP90:MMP2 complex is regulated remains speculative. Here, we report that the tissue in...

Heat shock triggers an instant reprogramming of gene and enhancer transcription, but whether cells encode a memory to stress, at the level of nascent transcription, has remained unknown. Here, we measured transcriptional response to acute heat stress in unconditioned cells and in daughters of cells that had been exposed to a single or multiple heat...

Cellular ability to maintain proper protein homeostasis (proteostasis) is essential for survival upon protein-damaging conditions. Heat shock transcription factor 2 (HSF2) is one of the human HSFs activated in response to proteotoxic stress. HSF2 is dispensable for cell survival during acute heat stress, but its amount and DNA-binding activity incr...

Cells respond to protein-damaging insults by activating heat shock factors (HSFs), key transcription factors of proteostasis. Abnormal HSF protein levels occur in cancer and neurodegenerative disorders, highlighting the importance of the tight control of HSF expression. HSF2 is a short-lived protein, but it is abundant in the prenatal brain cortex...

Heat shock factors (HSFs) are the main transcriptional regulators of the heat shock response and indispensable for maintaining cellular proteostasis. HSFs mediate their protective functions through diverse genetic programs, which are composed of genes encoding molecular chaperones and other genes crucial for cell survival. The mechanisms that are u...

Prostate cancer is a highly heterogeneous disease and the clinical outcome is varying. While current prognostic tools are regarded insufficient, there is a critical need for markers that would aid prognostication and patient risk-stratification. Heat shock transcription factor 1 (HSF1) is crucial for cellular homeostasis, but also a driver of oncog...

Heat shock factor 1 (HSF1) is an evolutionarily conserved transcription factor that initiates the cytoprotective heat shock response (HSR) and mediates a cancer-specific transcriptional program, which is comprised of over 500 genes and has been associated with poor clinical outcomes. HSF1 is thought to be regulated by molecular chaperones, includin...

Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction i...

Wnt-11 promotes cancer cell migration and invasion independently of β-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD8 is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-β signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cel...

Heat shock factor 1 (HSF1) initiates a broad transcriptional response to proteotoxic stress while also mediating a cancer-specific transcriptional program. HSF1 is thought to be regulated by molecular chaperones, including Heat Shock Protein 90 (HSP90). HSP90 is proposed to sequester HSF1 in unstressed cells, but visualization of this interaction i...

About 150 international scientists gathered in Turku, Finland, in August of 2017 for the eighth in a series of international congresses about the roles of stress proteins in biology and medicine. The scientific theme and title of the 2017 Congress was “Stress Management Mechanisms and Pathways.” The meeting covered a broad range of topics, reflecti...

The Notch signaling pathway is a key regulator of stem cells during development, and its deregulated activity is linked to developmental defects and cancer. Transcriptional activation of Notch target genes requires cleavage of the Notch receptor in response to ligand binding, production of the Notch intracellular domain (NICD1), NICD1 migration int...

Programs of gene expression are executed by a battery of transcription factors that coordinate divergent transcription from a pair of tightly linked core initiation regions of promoters and enhancers. Here, to investigate how divergent transcription is reprogrammed upon stress, we measured nascent RNA synthesis at nucleotide-resolution, and profile...

Defects in cellular protein homeostasis are associated with many severe and prevalent pathological conditions such as neurodegenerative diseases, muscle dystrophies, and metabolic disorders. One way to counteract these defects is to improve the protein homeostasis capacity through induction of the heat shock response. Despite numerous attempts to d...

Organisms are constantly exposed to acute and chronic stress conditions, which challenge the maintenance of protein homeostasis. Heat Shock Proteins (HSPs) function as molecular chaperones to stabilize protein structures, facilitate refolding of misfolded proteins, and prevent uncontrolled protein aggregation. Therefore, HSPs serve as the first and...

Aim: Sirtuins are proteins that connect energy metabolism, oxidative stress and aging. Expression of heat shock proteins (Hsps) is regulated by heat shock factors (HSFs) in response to various environmental and physiological stresses, such as oxidative stress. Oxidative stress accumulates during aging which makes cells more prone to DNA damage. Al...

Background: Cells have developed many ways to cope with external stress. One distinctive feature in acute proteotoxic stresses, such as heat shock (HS), is rapid post-translational modification of proteins by SUMOs (small ubiquitin-like modifier proteins; SUMOylation). While many of the SUMO targets are chromatin proteins, there is scarce informat...

Heat-shock factors (HSFs) are key transcriptional regulators in cell survival. Although HSF1 has been identified as a driver of carcinogenesis, HSF2 has not been explored in malignancies. Here, we report that HSF2 suppresses tumor invasion of prostate cancer (PrCa). In three-dimensional organotypic cultures and the in vivo xenograft chorioallantoic...

In mammals the stress-inducible expression of genes encoding heat shock proteins is under control of the heat shock transcription factor 1 (HSF1). Activation of HSF1 is a multistep process, involving trimerization, acquisition of DNA-binding and transcriptional activities, which coincide with several post-translational modifications. Stress-inducib...

Maintenance of cellular homeostasis depends upon several pathways that allow a cell to respond and adapt to both environmental stress and changes in metabolic status. New work in this issue of The EMBO Journal reveals a mechanism of cross talk between heat shock factor 1 (HSF1), the primary regulator of the proteotoxic stress response, and AMP-acti...

A collaborative workshop dedicated to the discussion of heat shock factors in stress response, development, and disease was held on April 22-24, 2014 at the Université Paris Diderot in Paris, France. Recent years have witnessed an explosion of interest in these highly conserved transcription factors, with biological roles ranging from environmental...

Unless mitigated, external and physiological stresses are detrimental for cells, especially in mitosis, resulting in chromosomal missegregation, aneuploidy, or apoptosis. Heat shock proteins (Hsps) maintain protein homeostasis and promote cell survival. Hsps are transcriptionally regulated by heat shock factors (HSFs). Of these, HSF1 is the master...

Prostate cancer (PrCa) is the most common malignancy in Western countries and account for the second highest mortality rate of all cancer forms in males. Specifically in late stage castration-resistant PrCa (CRPC), the signaling pathways that contribute to invasion and metastasis are poorly understood. The heat shock factors (HSFs) are a family of...

Heat shock factor 1 (HSF1) is an evolutionarily highly conserved transcription factor that coordinates stress-induced transcription and directs versatile physiological processes in eukaryotes. The central position of HSF1 in cellular homeostasis has been well demonstrated, mainly through its strong effect in transactivating genes that encode heat s...

The present invention is directed to methods of modulating HSF1 activity comprising modifying the acetylation of the DNA binding domain of the HSF1.

Significance We determined the transcriptional program that is rapidly provoked to counteract heat-induced stress and uncovered the broad range of molecular mechanisms that maintain cellular homeostasis under hostile conditions. Because transcriptional responses are directed in the complex chromatin environment that undergoes dramatic changes durin...

Highly conserved, molecular chaperones, known as Heat Shock Proteins (HSPs), assist in protein folding and perform quality‐control process. Impaired activity of HSPs results in uncontrolled protein aggregation. Inducible transcription of HSPs is driven by Heat Shock Response, mechanism strictly regulated by Heat Shock Factor 1 (HSF1). Upon proteoto...

ErbB4 is a receptor tyrosine kinase implicated in the development and homeostasis of the heart, central nervous system, and mammary gland. Cleavable isoforms of ErbB4 release a soluble intracellular domain (ICD) that can translocate to the nucleus and function as a transcriptional coregulator. In search of regulatory mechanisms of ErbB4 ICD functio...

Background: ErbB4 is a member of EGFR/ErbB family of receptor tyrosine kinases (RTK). ErbB4 is subjected to regulated intramembrane proteolysis (RIP), resulting in the release of a soluble ErbB4 intracellular domain (ICD) into the cytosol. ErbB4 ICD can translocate to the nucleus and function as a transcriptional coregulator. Although nuclear ErbB4...

The heat shock response is a primordial defense mechanism against cell stress and protein misfolding. It proceeds with the minimum number of mechanisms that any regulatory network must include, a stress-induced activation and a feedback regulation, and can thus be regarded as the archetype for a cellular regulatory process. We propose here a simple...

Heat shock factor 1 (HSF1) is an important transcription factor in cellular stress responses, cancer, aging, and deve