Genomic Heat Shock Element Sequences Drive Cooperative Human Heat Shock Factor 1 DNA Binding and Selectivity

Jaeger, Alex M.; Makley, Leah N.; Gestwicki, Jason E.; Thiele, Dennis J.

doi:10.1074/jbc.m114.591578

Cited by 56 publications

(45 citation statements)

References 33 publications

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“…Using fluorescence polarization and thermal denaturation profiling combined with quantitative chromatin immunoprecipitation assays, Jaeger et al . have demonstrated a role for specific orientations of extended HSE sequences in driving preferential HSF1 DNA binding to its target loci.…”

Section: Hsf1mentioning

confidence: 99%

Regulation of the mammalian heat shock factor 1

2017

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Living organisms are endowed with the capability to tackle various forms of cellular stress due to the presence of molecular chaperone machinery complexes that are ubiquitous throughout the cell. During conditions of proteotoxic stress, the transcription factor heat shock factor 1 (HSF1) mediates the elevation of heat shock proteins, which are crucial components of the chaperone complex machinery and function to ameliorate protein misfolding and aggregation and restore protein homeostasis. In addition, HSF1 orchestrates a versatile transcriptional programme that includes genes involved in repair and clearance of damaged macromolecules and maintenance of cell structure and metabolism, and provides protection against a broad range of cellular stress mediators, beyond heat shock. Here, we discuss the structure and function of the mammalian HSF1 and its regulation by post-translational modifications (phosphorylation, sumoylation and acetylation), proteasomal degradation, and smallmolecule activators and inhibitors.

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Section: Hsf1mentioning

confidence: 99%

Regulation of the mammalian heat shock factor 1

2017

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“…The cellular response to hyperthermia is mediated by trimerization of the temperature-sensitive transcription factor Heat Shock Factor 1 (HSF1) and its subsequent binding to DNA motifs termed Heat Shock Elements (HSEs). HSEs are comprised of multiple inverted repeats of the consensus sequence 5'-nGAAn-3' 28,29 and are arrayed upstream of HSPs thereby enabling their upregulation following thermal stress 30 . The response of endogenous HSP genes is selective, but not specific, for heat as their promoters contain additional regulatory elements (e.g., hypoxia response elements 31 , metal-responsive elements 32 ) that mediate transcription following exposure to a diverse set of cues including hypoxia 33 , heavy metals 34 , and mechanical force 35 .…”

Section: Engineering Thermal-specific Gene Switchesmentioning

confidence: 99%

Remote control of CAR T cell therapies by thermal targeting

Miller

Sun

Harris

et al. 2020

Preprint

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The limited ability to control anti-tumor activity within tumor sites contributes to poor CAR T cell responses against solid malignancies. Systemic delivery of biologic drugs such as cytokines can augment CAR T cell activity despite off-target toxicity in healthy tissues that narrow their therapeutic window. Here we develop a platform for remote control of CAR T therapies by thermal targeting. To enable CAR T cells to respond to heat, we construct synthetic thermal gene switches that trigger expression of transgenes in response to mild elevations in local temperature (40-42 °C) but not to orthogonal cellular stresses such as hypoxia. We show that short pulses of heat (15-30 min) lead to more than 60-fold increases in gene expression without affecting key T cell functions including proliferation, migration, and cytotoxicity. We demonstrate thermal control of broad classes of immunostimulatory agents including CARs, Bispecific T cell Engagers (BiTEs), and cytokine superagonists to enhance proliferation and cell targeting. In mouse models of adoptive transfer, photothermal targeting of intratumoral CAR T cells to control the production of an IL-15 superagonist significantly enhances anti-tumor activity and overall survival. We envision that thermal targeting could improve the safety and efficacy of next-generation therapies by allowing remote control of CAR T cell activity.

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“…We did not detect CpG methylation in a region driving basal transcriptional activity. However, region-1, which contains some sequences similar to heat shock transcription factor 1 (HSF1) binding motifs ( Jaeger et al, 2014;Trinklein et al, 2004), was found to be methylated in all cell lines (Fig. 5A), suggesting that methylation of this region could have some regulatory effects.…”

Section: Cpg Methylation In the 5¢-flanking Region Of Hlj1mentioning

confidence: 99%

“…4). According to our combined bisulfite restriction analysis (COBRA) results, the 5¢-flanking region having sequences similar to HSF1 binding motifs (heat shock elements [HSEs]) was found to be methylated in all breast cell lines ( Jaeger et al, 2014;Trinklein et al, 2004) (Fig. 5A).…”

Section: Figmentioning

confidence: 99%

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HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer

Acun

Doberstein

Habermann

et al. 2017

OMICS: A Journal of Integrative Biology

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Breast cancer is the most common cancer type and cause of cancer-related mortality among women worldwide. New biomarker discovery is crucial for diagnostic innovation and personalized medicine in breast cancer. Heat shock proteins (HSPs) have been increasingly reported as biomarkers and potential drug targets for cancers. HLJ1 (DNAJB4) belongs to the DNAJ (HSP40) family of HSPs and is regarded as a tumor suppressor gene in lung, colon, and gastric cancers. However, the role of the HLJ1 gene in breast cancer is currently unknown. We evaluated the role of the HLJ1 gene in breast cancer progression by analyzing its in vitro and in vivo expression and its genetic/epigenetic alterations. HLJ1 expression was found to be reduced or lost in breast cancer cell lines (SK-BR-3, MDA-MB-231, ZR-75-1) compared with the nontumorigenic mammary epithelial cell line (MCF 10A). In a clinical context for breast cancer progression, the HLJ1 expression was significantly less frequent in invasive breast carcinoma samples (n = 230) compared with normal breast tissue (n = 100), benign neoplasia (n = 53), and ductal carcinoma in situ (n = 21). In methylation analyses by the combined bisulfite restriction analysis assay, the CpG island located in the 5¢-flanking region of the HLJ1 gene was found to be methylated in breast cancer cell lines. HLJ1 expression was restored in the ZR-75-1 cell line by DNA demethylating agent 5-Aza-2¢-deoxycytidine (5-AzadC) and histone deacetylase inhibitor trichostatin A. These new observations support the idea that HLJ1 is a tumor suppressor candidate and potential biomarker for breast cancer. Epigenomic mechanisms such as CpG methylation and histone deacetylation might contribute to downregulation of HLJ1 expression. We call for future functional, epigenomic, and clinical studies to ascertain the contribution of HLJ1 to breast cancer pathogenesis and, importantly, evaluate its potential for biomarker development in support of personalized medicine diagnostic innovation in clinical oncology.

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Genomic Heat Shock Element Sequences Drive Cooperative Human Heat Shock Factor 1 DNA Binding and Selectivity

Cited by 56 publications

References 33 publications

Regulation of the mammalian heat shock factor 1

Regulation of the mammalian heat shock factor 1

Remote control of CAR T cell therapies by thermal targeting

HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer

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