Caenorhabditis elegans Heterochromatin protein 1 (HPL-2) links developmental plasticity, longevity and lipid metabolism

Meister, Peter; Schott, Sonia; Bedet, Cécile; Xiao, Yu; Rohner, Sabine; Bodennec, Selena; Hudry, Bruno; Molin, Laurent; Solari, Florence; Gasser, Susan M.; Palladino, Francesca

doi:10.1186/gb-2011-12-12-r123

Cited by 53 publications

(30 citation statements)

References 108 publications

(135 reference statements)

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“…Therefore, the absence of HPL-2 improves survival following the induction of acute ER stress by two distinct stressors. Importantly, increased resistance to ER stress does not reflect a general resistance to stress conditions, as hpl-2 mutants are inheritently sensitive to thermal stress (8), more sensitive to osmotic stress (10), but unaltered in their response to oxidative stress (7).…”

Section: Resultsmentioning

confidence: 99%

“…Heterochromatin protein 1 (HP1) family proteins are conserved epigenetic regulators that control gene expression depending on the chromatin context (6). We have previously shown that the Caenorhabditis elegans HP1 homolog heterochromatin protein like-2 (HPL-2) plays a regulatory role in the dauer decision, an alternative developmental program that worms undergo under stressful conditions (7). In this study, we show that animals lacking HPL-2 are more resistant to induced ER stress, an effect mediated by the XBP-1/IRE-1 branch of the UPR and autophagy.…”

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confidence: 99%

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The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

Kozlowski

Garvis

Bedet

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cellular adaptation to environmental changes and stress relies on a wide range of regulatory mechanisms that are tightly controlled at several levels, including transcription. Chromatin structure and chromatin binding proteins are important factors contributing to the transcriptional response to stress. However, it remains largely unknown to what extent specific chromatin factors influence the response to distinct forms of stress in a developmental context. One of the best characterized stress response pathways is the unfolded protein response (UPR), which is activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). Here, we show that Caenorhabditis elegans heterochromatin protein like-2 (HPL-2), the homolog of heterochromatin protein 1 (HP1), downregulates the UPR in the intestine. Inactivation of HPL-2 results in an enhanced resistance to ER stress dependent on the X-box binding protein 1 (XBP-1)/inositol requiring enzyme 1 branch of the UPR and the closely related process of autophagy. Increased resistance to ER stress in animals lacking HPL-2 is associated with increased basal levels of XBP-1 activation and ER chaperone expression under physiological conditions, which may in turn activate an adaptive response known as ER hormesis. HPL-2 expression in intestinal cells is sufficient to rescue stress resistance, whereas expression in neuronal cells negatively influenced the ER stress response through a cell-nonautonomous mechanism. We further show that the retinoblastoma protein homolog LIN-35 and the LIN-13 zinc finger protein act in the same pathway as HPL-2 to limit the ER stress response. Altogether, our results point to multiple functions for HP1 in different cell types to maintain ER homeostasis.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

Kozlowski

Garvis

Bedet

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…However, we could not detect ectopic PGL-1 or HTP-3 in these worms. hpl-2 mutants were previously reported to have a modest increase in lifespan and to express genes that control dauer formation, lipid metabolism, and longevity in addition to germ-line genes in their soma (25). Raising synMuv B mutants at 24°C caused a dramatic increase in the level of ectopic germ-line gene expression, but did not result in an increase in lifespan (Fig.…”

Section: Synmuv B Mutants Ectopically Express Germ-line Factors But Amentioning

confidence: 99%

Reevaluation of whether a soma–to–germ-line transformation extends lifespan in Caenorhabditis elegans

Knutson

Rechtsteiner

Strome

2016

Proc. Natl. Acad. Sci. U.S.A.

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The germ lineage is considered to be immortal. In the quest to extend lifespan, a possible strategy is to drive germ-line traits in somatic cells, to try to confer some of the germ lineage's immortality on the somatic body. Notably, a study in Caenorhabditis elegans suggested that expression of germ-line genes in the somatic cells of long-lived daf-2 mutants confers some of daf-2's long lifespan. Specifically, mRNAs encoding components of C. elegans germ granules (P granules) were up-regulated in daf-2 mutant worms, and knockdown of individual P-granule and other germ-line genes in daf-2 young adults modestly reduced their lifespan. We investigated the contribution of a germ-line program to daf-2's long lifespan and also tested whether other mutants known to express germ-line genes in their somatic cells are long-lived. Our key findings are as follows. (i) We could not detect P-granule proteins in the somatic cells of daf-2 mutants by immunostaining or by expression of a P-granule transgene. (ii) Whole-genome transcript profiling of animals lacking a germ line revealed that germ-line transcripts are not up-regulated in the soma of daf-2 worms compared with the soma of control worms. (iii) Simultaneous removal of multiple P-granule proteins or the entire germ-line program from daf-2 worms did not reduce their lifespan. (iv) Several mutants that robustly express a broad spectrum of germ-line genes in their somatic cells are not long-lived. Together, our findings argue against the hypothesis that acquisition of a germ-cell program in somatic cells increases lifespan and contributes to daf-2's long lifespan.germ line | aging | C. elegans | daf-2 | P granules G erm and soma are the two most fundamentally different cell types found in multicellular organisms (1). Germ cells are totipotent and constitute the only immortal lineage, capable of generating entire new organisms generation after generation, whereas somatic cells differentiate into specialized cell types and are mortal, senescing and dying each generation. Maintaining the proper identity of these cell types is essential for propagation of species, and molecular barriers at both the transcriptional and translational levels have evolved to ensure the germ-soma distinction (1). Removal of these barriers in germ cells can lead to both expression of somatic factors and sterility (2-4), whereas removal of these barriers in somatic cells is associated with reentry into the cell cycle and cancer (5, 6). Despite these barriers, it is unknown whether some cell types can tolerate partial fate switching and perhaps adopt traits of other cell types to benefit the organism.An attractive possibility is that acquisition of a germ-cell program by the somatic body can capture some of the immortality of the germ lineage and extend lifespan (7,8). Indeed, a study in Caenorhabditis elegans supports that possibility (9). In C. elegans, inhibition of the insulin-like signaling pathway by a mutation in daf-2 doubles lifespan through activation of the FOXO transcription factor DAF-16...

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“…Despite a clear connection between heterochromatin maintenance and lifespan extension (Feser et al ., 2010; Meister et al ., 2011; Larson et al ., 2012; Jiang et al ., 2013), the cause of heterochromatin loss and how it leads to cellular damage and aging is not well understood. Generally speaking, heterochromatin loss would lead to a mis‐expression of genes that are normally repressed, which could result in age‐ associated cellular defects.…”

Section: Introductionmentioning

confidence: 99%

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

et al. 2016

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SummaryEukaryotic genomes contain transposable elements (TE) that can move into new locations upon activation. Since uncontrolled transposition of TEs, including the retrotransposons and DNA transposons, can lead to DNA breaks and genomic instability, multiple mechanisms, including heterochromatin‐mediated repression, have evolved to repress TE activation. Studies in model organisms have shown that TEs become activated upon aging as a result of age‐associated deregulation of heterochromatin. Considering that different organisms or cell types may undergo distinct heterochromatin changes upon aging, it is important to identify pathways that lead to TE activation in specific tissues and cell types. Through deep sequencing of isolated RNAs, we report an increased expression of many retrotransposons in the old Drosophila fat body, an organ equivalent to the mammalian liver and adipose tissue. This de‐repression correlates with an increased number of DNA damage foci and decreased level of Drosophila lamin‐B in the old fat body cells. Depletion of the Drosophila lamin‐B in the young or larval fat body results in a reduction of heterochromatin and a corresponding increase in retrotransposon expression and DNA damage. Further manipulations of lamin‐B and retrotransposon expression suggest a role of the nuclear lamina in maintaining the genome integrity of the Drosophila fat body by repressing retrotransposons.

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Caenorhabditis elegans Heterochromatin protein 1 (HPL-2) links developmental plasticity, longevity and lipid metabolism

Cited by 53 publications

References 108 publications

The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

Reevaluation of whether a soma–to–germ-line transformation extends lifespan in Caenorhabditis elegans

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

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