The longevity SNP rs2802292 uncovered: HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer

Grossi, Valentina; Forte, Giovanna; Sanese, Paola; Peserico, Alessia; Tezil, Tuğsan; Signorile, Martina Lepore; Fasano, Candida; Lovaglio, Rosaura; Bagnulo, Rosanna; Loconte, Daria Carmela; Susca, Francesco; Resta, Nicoletta; Simone, Cristiano

doi:10.1093/nar/gky331

Cited by 61 publications

(50 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In carriers of the G allele of a longevity variant of FOXO3 , the FOXO3 gene was physically closer to its neighboring genes, and when exposed to stress, FOXO3 mRNA expression in lymphoblastoid cell lines derived from carriers increased more than in cell lines derived from non-carriers 62 . In line with those findings, another study showed that the same genetic variant has enhancer functions and that the G allele allows the creation of a novel transcription factor binding site, which induces FOXO3 mRNA expression in response to diverse stress stimuli 63 .…”

Section: Foxo3 and The Genetics Of Longevitymentioning

confidence: 57%

Recent advances in understanding the role of FOXO3

et al. 2018

View full text Add to dashboard Cite

The forkhead box O3 (FOXO3, or FKHRL1) protein is a member of the FOXO subclass of transcription factors. FOXO proteins were originally identified as regulators of insulin-related genes; however, they are now established regulators of genes involved in vital biological processes, including substrate metabolism, protein turnover, cell survival, and cell death. FOXO3 is one of the rare genes that have been consistently linked to longevity in in vivo models. This review provides an update of the most recent research pertaining to the role of FOXO3 in (i) the regulation of protein turnover in skeletal muscle, the largest protein pool of the body, and (ii) the genetic basis of longevity. Finally, it examines (iii) the role of microRNAs in the regulation of FOXO3 and its impact on the regulation of the cell cycle.

show abstract

Section: Foxo3 and The Genetics Of Longevitymentioning

confidence: 57%

Recent advances in understanding the role of FOXO3

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Furthermore, although the human PMAIP1 gene lacks a perfect HSE consensus sequence, HSF1 also exhibited increased binding to the HSE-like motif located in the intron in response to heat shock concomitant with upregulation of the gene expression. Transcription activation is usually associated with the binding of HSF1 to target gene promoters, although there are also reports showing the involvement of HSF1 in transcription regulation through intronic sequences [39][40][41]. This mode of regulation could rely on chromatin looping between intronic HSE and other regulatory sequences (e.g., enhancers) as it was shown by Grossi et al [40].…”

Section: Discussionmentioning

confidence: 99%

Pro-death signaling of cytoprotective heat shock factor 1: upregulation of NOXA leading to apoptosis in heat-sensitive cells

et al. 2020

View full text Add to dashboard Cite

Heat shock can induce either cytoprotective mechanisms or cell death. We found that in certain human and mouse cells, including spermatocytes, activated heat shock factor 1 (HSF1) binds to sequences located in the intron(s) of the PMAIP1 (NOXA) gene and upregulates its expression which induces apoptosis. Such a mode of PMAIP1 activation is not dependent on p53. Therefore, HSF1 not only can activate the expression of genes encoding cytoprotective heat shock proteins, which prevents apoptosis, but it can also positively regulate the proapoptotic PMAIP1 gene, which facilitates cell death. This could be the primary cause of hyperthermia-induced elimination of heat-sensitive cells, yet other pro-death mechanisms might also be involved.

show abstract

“…Functional studies suggested the existence of an HSF1-FOXO3 axis in human cells that could be involved in stress response 203 . FOXO3 became physically connected, through chromatin looping, with 46 other genes on chromosome 6 thus forming an aging hub 199 .…”

Section: Igf-1 and Foxo3mentioning

confidence: 99%

Genetics of Human Longevity Within an Eco-Evolutionary Nature-Nurture Framework

Giuliani

Garagnani

Franceschi

2018

Circulation Research

View full text Add to dashboard Cite

Genetics of human longevity within an eco-evolutionary nature-nurture framework. -Circulation Research 2018 ; 123(7) : 745-772.The final published version is available online at: https://www.ahajournals.org/ ABSTRACTHuman longevity is a complex trait, and to disentangle its basis has a great theoretical and practical consequence for biomedicine. The genetics of human longevity is still poorly understood, despite a number of investigations that used different strategies and protocols. Here we argue that such rather disappointing harvest is largely due to the extraordinary complexity of the longevity phenotype in humans. The capability to reach the extreme decades of human lifespan appears to be the result of an intriguing mixture of geneenvironment interactions. Accordingly, the genetics of human longevity is here described as a highly context-dependent phenomenon, within a new integrated, ecological and evolutionary perspective, and is presented as a dynamic process, both historically and individually. The available literature has been scrutinized within this perspective, paying particular attention to factors (sex, individual biography, family, population ancestry, social structure, economic status and education, among others) that have been relatively neglected. The strength and limitations of the most powerful and used tools, such as GWAS and whole-genome sequencing, have been discussed, focusing on prominently emerged genes and regions, such as APOE, FOXO3, IL-6, IGF-1, chromosome 9p21, 5q33.3 and somatic mutations among others. The major results of this approach suggest that: i) the genetics of longevity is highly population-specific; ii) small-effect alleles, pleiotropy and the "complex allele timing" likely play a major role; iii) genetic risk factors are age-specific and need to be integrated in the light of the geroscience perspective; iv) a close relationship between genetics of longevity and genetics of age-related diseases (especially cardiovascular diseases) do exist. Finally, the urgent need of a global approach to the largely unexplored interactions between the three genetics of human body, i.e. nuclear, mitochondrial and microbiomes, is stressed. We surmise that the comprehensive approach here presented will help in increasing the above-mentioned harvest.

show abstract

The longevity SNP rs2802292 uncovered: HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer

Cited by 61 publications

References 55 publications

Recent advances in understanding the role of FOXO3

Recent advances in understanding the role of FOXO3

Pro-death signaling of cytoprotective heat shock factor 1: upregulation of NOXA leading to apoptosis in heat-sensitive cells

Genetics of Human Longevity Within an Eco-Evolutionary Nature-Nurture Framework

Contact Info

Product

Resources

About