Nuclear stress granules: the awakening of a sleeping beauty?

Nuclear stress granules are subnuclear compartments that form in response to heat shock and other stress stimuli. Although many components of nuclear stress granules have been identified, including HSF1 and pre-mRNA processing factors, their function remains a mystery. A paper in this issue describes the stress-induced transcriptional activation of one of the nuclear stress granule target sites, a heterochromatic region that has been considered silent (Jolly et al., 2004). These intriguing findings will certainly give the research of these structures a new twist

Stressiproteiinien merkitys ja käyttö lääkekehityksen kohdemolekyyleinä

Proteiinihomeostaasi eli solujen kyky ylläpitää proteiinimolekyylien oikeaa laskostumista ja toiminnallisuutta on erottamattomasti yhteydessä ihmisen terveyteen. Ikääntyminen, fysiologinen stressi ja mutatoituneiden proteiinien ilmentyminen haastavat solun proteiinihomeostaasin, minkä seurauksena riski sairastua laskostumisvirheistä ja proteiinikertymistä johtuviin sairauksiin lisääntyy. Molekyylikaitsijat eli stressiproteiinit, kuten lämpösokkiproteiinit, ovat proteiinihomeostaasin keskeisimpiä säätelijöitä, ja niiden tehtävä on ohjata proteiinien laskostumista, sijaintia ja hajotusta. Virheellisesti säätynyt stressivaste ja yleinen proteiinien laadunvarmistuskoneiston heikkeneminen on yhdistetty useisiin kroonisiin tautitiloihin, kuten hermoston rappeumatauteihin ja syöpiin. Siksi stressivasteiden farmakologisesta säätelystä odotetaan apua yhä laajenevan sairausjoukon hoitoon.</p

Molecular Mechanisms of Heat Shock Factors in Cancer

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 past decade it has become evident that their activities are rewired during tumorigenesis. This review focuses on the expression patterns and functions of HSF1, HSF2, and HSF4 in specific cancer types, highlighting the mechanisms by which the regulatory functions of these transcription factors are modulated. Recently developed therapeutic approaches that target HSFs are also discussed

Versatile Functions of Heat Shock Factors: It is Not All About Stress

Organisms are constantly exposed to acute and chronic stress conditions, which challenge the maintenance of protein homeostasis. Heat ShockProteins (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 last line ofdefense in the events of proteotoxic stresses. The stress-inducible expression of HSPs, which is a hallmark of the heat shock response, is understrict control of evolutionary conserved transcription factors, known as Heat Shock Factors (HSFs). Invertebrates have only a single HSF, whereas the HSF family in vertebrates consists of multiple members. Direct interactions of HSFs with various proteins, including HSPs, chromatin-associated proteins, and other HSF family members as well as their complex post-translational modifications, allow these transcription factors to function not only in stress responses but also in many other biological processes. For example, mammalian HSF1, HSF2 and HSF4 are fundamental for normal organismal development and healthy aging. Moreover, recent discoveries have highlighted the importance of HSFs in tumorigenesis, neurodegeneration, and metabolic disorders, which positions them as promising therapeutic targets in multiple human diseases. In this review, we focus on recent advances in the HSF biology and discuss the functional impact of HSFs on stress responses, development, aging, and age-related pathologies.</div

Interplay between mammalian heat shock factors 1 and 2 in physiology and pathology

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 neurodegenerative disorders and cancer, highlighting their importance in physiology and pathology. However, it is still unclear how HSFs are regulated and how they choose their specific target genes under different conditions. Posttranslational modifications and interplay among the HSF family members have been shown to be key regulatory mechanisms for these transcription factors. In this review, we focus on the mammalian HSF1 and HSF2, including their interplay, and provide an updated overview of the advances in understanding how HSFs are regulated and how they function in multiple processes of development, aging, and disease. We also discuss HSFs as therapeutic targets, especially the recently reported HSF1 inhibitors

Quantifying RNA synthesis at rate-limiting steps of transcription using nascent RNA-sequencing data

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-proximal regions, divergent transcripts, gene bodies, and termination windows, and (3) measure distribution of transcription machineries and regulatory proteins across functional genomic regions. This protocol tracks engaged transcription complexes across functional genomic regions demonstrated in human K562 erythroleukemia cells.</p

HSFs drive transcription of distinct genes and enhancers during oxidative stress and heat shock

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, HSF1 and HSF2, coordinate transcription at genes and enhancers upon oxidative stress and heat shock. We show that pause-release of RNA polymerase II (Pol II) is a universal mechanism regulating gene transcription in stressed cells, while enhancers are activated at the level of Pol II recruitment. Moreover, besides functioning as conventional promoter-binding transcription factors, HSF1 and HSF2 bind to stress-induced enhancers to trigger Pol II pause-release from poised gene promoters. Importantly, HSFs act at distinct genes and enhancers in a stress type-specific manner. HSF1 binds to many chaperone genes upon oxidative and heat stress but activates them only in heat-shocked cells. Under oxidative stress, HSF1 localizes to a unique set of promoters and enhancers to trans-activate oxidative stress-specific genes. Taken together, we show that HSFs function as multi-stress-responsive factors that activate distinct genes and enhancers when encountering changes in temperature and redox state

Therapeutic Potential of Targeting the SUMO Pathway in Cancer

The small ubiquitin-like modifier (SUMO) pathway regulates the hallmark properties of cancer cells. Moreover, alterations in activity and in levels of SUMO machinery components have been observed in human cancer. Due to the reversible nature of this post-translational protein modification, the balance between SUMOylation and the removal of SUMO is critical. Early-phase clinical trials are currently evaluating the safety and efficacy of SUMO pathway inhibition in cancer patients. In this comprehensive review, we critically discuss the potential of targeting the SUMO pathway as a therapeutic option for cancer. </p

Global SUMOylation on active chromatin is an acute heat stress response restricting transcription

ArticleBackground 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 information on chromatin binding of SUMOylated proteins in HS and the role of chromatin SUMOylation in the regulation of transcription. Results We mapped HS-induced genome-wide changes in chromatin occupancy of SUMO-2/3-modified proteins in K562 and VCaP cells using ChIP-seq. Chromatin SUMOylation was further correlated with HS-induced global changes in transcription using GRO-seq and RNA polymerase II (Pol2) ChIP-seq along with ENCODE data for K562 cells. HS induced a rapid and massive rearrangement of chromatin SUMOylation pattern: SUMOylation was gained at active promoters and enhancers associated with multiple transcription factors, including heat shock factor 1. Concomitant loss of SUMOylation occurred at inactive intergenic chromatin regions that were associated with CTCF-cohesin complex and SETDB1 methyltransferase complex. In addition, HS triggered a dynamic chromatin binding of SUMO ligase PIAS1, especially onto promoters. The HS-induced SUMOylation on chromatin was most notable at promoters of transcribed genes where it positively correlated with active transcription and Pol2 promoter-proximal pausing. Furthermore, silencing of SUMOylation machinery either by depletion of UBC9 or PIAS1 enhanced expression of HS-induced genes. Conclusions HS-triggered SUMOylation targets promoters and enhancers of actively transcribed genes where it restricts the transcriptional activity of the HS-induced genes. PIAS1-mediated promoter SUMOylation is likely to regulate Pol2-associated factors in HS.Publisher’s pd