Heat shock factor (HSF) is an evolutionarily conserved stress‐response regulator that activates the transcription of heat shock protein genes, whose products maintain protein homeostasis under normal physiological conditions, as well as under conditions of stress. The promoter regions of the target genes contain a heat shock element consisting of multiple inverted repeats of the pentanucleotide sequence nGAAn. A single HSF of yeast can bind to heat shock elements that differ in the configuration of the nGAAn units and can regulate the transcription of various genes that function not only in stress resistance, but also in a broad range of biological processes. Mammalian cells have four HSF family members involved in different, but in some cases similar, biological functions, including stress resistance, cell differentiation and development. Mammalian HSF family members exhibit differential specificity for different types of heat shock elements, which, together with cell type‐specific expression of HSFs is important in determining the target genes of each HSF. This minireview focuses on the molecular mechanisms of DNA recognition, chromatin modulation and gene expression by yeast and mammalian HSFs.
Binding of heat shock factors (Hsfs) to heat shock elements (HSEs) leads to transcriptional regulation of heat shock genes. Genome-wide, 953 rice genes contain perfect-type, 695 genes gap-type and 1584 genes step-type HSE sequences in their 1-kb promoter region. The rice genome contains 13 class A, eight class B and four class C Hsfs (OsHsfs) and has OsHsf26 (which is of variant type) genes. Chemical cross-linking analysis of in vitro synthesized OsHsf polypeptides showed formation of homotrimers of OsHsfA2c, OsHsfA9 and OsHsfB4b proteins. Binding analysis of polypeptides with oligonucleotide probes containing perfect-, gap-, and step-type HSE sequences showed that OsHsfA2c, OsHsfA9 and OsHsfB4b differentially recognize various model HSEs as a function of varying reaction temperatures. The homomeric form of OsHsfA2c and OsHsfB4b proteins was further noted by the bimolecular fluorescence complementation approach in onion epidermal cells. In yeast two-hybrid assays, OsHsfB4b showed homomeric interaction as well as distinct heteromeric interactions with OsHsfA2a, OsHsfA7, OsHsfB4c and OsHsf26. Transactivation activity was noted in OsHsfA2c, OsHsfA2d, OsHsfA9, OsHsfC1a and OsHsfC1b in yeast cells. These differential patterns pertaining to binding with HSEs and protein-protein interactions may have a bearing on the cellular functioning of OsHsfs under a range of different physiological and environmental conditions. Structured digital abstractl HSFA2C binds to HSFA2C by cross-linking study (View interaction) l HSFA2C physically interacts with HSFA2C by bimolecular fluorescence complementation (View interaction) l HSFB4B physically interacts with HSFB4B by bimolecular fluorescence complementation (View interaction) l HSFA2A physically interacts with HSFB4B by two hybrid (View interaction) l HSFB4B binds to HSFB4B by cross-linking study (View interaction) l HSFB4B physically interacts with HSF26 by two hybrid (View interaction) l HSFA9 binds to HSFA9 by cross-linking study (View interaction) l HSFA7 physically interacts with HSFB4B by two hybrid (View interaction) l HSFB4B physically interacts with HSFB4C by two hybrid (View interaction) l HSFB4B physically interacts with HSFB4B by two hybrid (View interaction) Abbreviations 3-AT, 3-amino-1,2,4-triazole; BiFC, bimolecular fluorescence complementation; EGS, ethylglycol bis(succinimidylsuccinate); EMSA, electrophoretic mobility shift assay; HS, heat shock; HSE, heat shock element; Hsf, heat shock transcription factor; Hsp, heat shock protein.
HSF (heat-shock transcription factor) trimers bind to the HSE (heat-shock element) regulatory sequence of target genes and regulate gene expression. A typical HSE consists of at least three contiguous inverted repeats of the 5-bp sequence nGAAn. Yeast HSF is able to recognize discontinuous HSEs that contain gaps in the array of the nGAAn sequence; however, hHSF1 (human HSF1) fails to recognize such sites in vitro, in yeast and in HeLa cells. In the present study, we isolated suppressors of the temperature-sensitive growth defect of hHSF1-expressing yeast cells. Intragenic suppressors contained amino acid substitutions in the DNA-binding domain of hHSF1 that enabled hHSF1 to regulate the transcription of genes containing discontinuous HSEs. The substitutions facilitated hHSF1 oligomerization, suggesting that the DNA-binding domain is important for this conformational change. Furthermore, other oligomerization-prone derivatives of hHSF1 were capable of recognizing discontinuous HSEs. These results suggest that modulation of oligomerization is important for the HSE specificity of hHSF1 and imply that hHSF1 possesses the ability to bind to and regulate gene expression via various types of HSEs in diverse cellular processes.
Edited by Ivan Sadowski Keywords:Alternative splicing Heat shock response Protein-DNA interaction Protein-protein interaction Transcription factor a b s t r a c t Heat shock transcription factor (HSF), an evolutionarily conserved heat-responsive regulator, binds to heat shock elements (HSEs) comprising continuous inverted repeats of the pentamer nGAAn. Here, we analyzed DNA-binding ability, particularly for the discontinuously arranged nGAAn units, of HSFs from various organisms, including Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, and Danio rerio. Among these, only C. elegans HSF failed to bind the discontinuous nGAAn units, which suggests that the target genes of HSFs in many, but not all, organisms contain discontinuous HSEs, as well as continuous HSEs. Further analysis of alternatively spliced HSF isoforms showed the importance of the C-terminal region in HSF-HSE interaction.
Heat shock transcription factor HSF4 is necessary for ocular lens development and fiber cell differentiation. Mutations of the human HSF4 gene have been implicated in congenital and age-related cataracts. Here, we show that HSF4 activates transcription of genes encoding crystallins and beaded filament structural proteins in lens epithelial cells. Five missense mutations that have been associated with congenital cataract inhibited DNA-binding of HSF4, which demonstrates the relationship between HSF4 mutations, loss of lens protein gene expression, and cataractogenesis. However, two missense mutations that have been associated with age-related cataract did not or only slightly alter HSF4 activity, implying that other genetic and environmental factors affect the functions of these mutant proteins.
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