Aged Worms Erase Epigenetic History
2011; Cell Press; Volume: 14; Issue: 2 Linguagem: Inglês
10.1016/j.cmet.2011.07.008
ISSN1932-7420
AutoresVictoria V. Lunyak, Brian K. Kennedy,
Tópico(s)CRISPR and Genetic Engineering
ResumoDefining the molecular events that precipitate multisystem decline is an important component of aging research. In this issue, Jin et al., 2011Jin C. Li J. Green C.D. Yu X. Han D. Xian B. Wang D. Huang X. Cao X. Yan Z. et al.Cell Met. 2011; 14 (this issue): 161-172Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar show that increased expression of the histone demethylase, utx-1, causes genome-wide decreases in histone H3K27 trimethylation, which includes the insulin/IGF-1 signaling (IIS) pathway that promotes aging. Defining the molecular events that precipitate multisystem decline is an important component of aging research. In this issue, Jin et al., 2011Jin C. Li J. Green C.D. Yu X. Han D. Xian B. Wang D. Huang X. Cao X. Yan Z. et al.Cell Met. 2011; 14 (this issue): 161-172Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar show that increased expression of the histone demethylase, utx-1, causes genome-wide decreases in histone H3K27 trimethylation, which includes the insulin/IGF-1 signaling (IIS) pathway that promotes aging. Complex systems rely on solid infrastructure. Information has to be accessible, communicable, and translated into efficient operational output. Biological aging of a complex system (a human being or even a C. elegans worm) may be a progressive failure at each of these levels, from flawed cellular record keeping to breakdown of information transmission and an inability to mount a cellular response to maintain function or adapt to change (Figure 1). In this issue, Jin et al. identify a mechanism by which information, in the form of epigenetic marks, is lost with age in C. elegans and propose that this record-keeping failure drives signal-transduction pathways in a manner that promotes aging (Jin et al., 2011Jin C. Li J. Green C.D. Yu X. Han D. Xian B. Wang D. Huang X. Cao X. Yan Z. et al.Cell Met. 2011; 14 (this issue): 161-172Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). Eukaryotic genomes are repetitively packaged into chromatin by nucleosomes and nuclear architecture is regulated by specific covalent posttranslational modifications (PTMs) of histone proteins, the basic nucleosomal components (Kouzarides, 2007Kouzarides T. Cell. 2007; 128: 693-705Abstract Full Text Full Text PDF PubMed Scopus (8067) Google Scholar). Local histone PTMs direct inheritance and propagation of the chromatin states, which control cell-type specific transcriptional responses. The mechanisms responsible for cell-type specific chromatin establishment and maintenance in dividing cells, hence epigenetic inheritance of chromatin state, still remains largely enigmatic and is thought to rely upon a highly coordinated interplay between enzymes that catalyze (writers), and remove (erasers) histone PTMs, as well as, the proteins that recognize and bind to those modifications (readers) (Yun et al., 2011Yun M. Wu J. Workman J.L. Li B. Cell Res. 2011; 21: 564-578Crossref PubMed Scopus (401) Google Scholar). Tightly controlled equilibria between these molecular players may be especially relevant during aging, where chromatin deterioration is a prime suspect in impaired cellular function. It is believed that chromatin structure not only plays an important regulatory role in aging, but also that multiple aging-related signaling pathways in turn have complex interplay with chromatin, both influencing and being influenced by PTMs. For instance, methylation of histone lysine residues is dynamically regulated by the opposing activities of substrate-specific histone lysine methyltransferases (writers) and demethylases (erasers) (Allis et al., 2007Allis C.D. Berger S.L. Cote J. Dent S. Jenuwien T. Kouzarides T. Pillus L. Reinberg D. Shi Y. Shiekhattar R. et al.Cell. 2007; 131: 633-636Abstract Full Text Full Text PDF PubMed Scopus (744) Google Scholar). These enzymes have recently been shown to modulate germ-line immortality (LSD1) and longevity (ASH1) (Katz et al., 2009Katz D.J. Edwards T.M. Reinke V. Kelly W.G. Cell. 2009; 137: 308-320Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, Jin et al., 2011Jin C. Li J. Green C.D. Yu X. Han D. Xian B. Wang D. Huang X. Cao X. Yan Z. et al.Cell Met. 2011; 14 (this issue): 161-172Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar and references therein). Jin et al. demonstrates an aging role for another histone demethylase, UTX-1, in C. elegans. UTX-1/KMT6A demethylase activity along with JMJD3/KDM6B is critical for removal of transcriptionally repressive trimetylation on lysine 27 of histone H3 (H3K27me3) (Agger et al., 2007Agger K. Cloos P.A. Christensen J. Pasini D. Rose S. Rappsilber J. Issaeva I. Canaani E. Salcini A.E. Helin K. Nature. 2007; 449: 731-734Crossref PubMed Scopus (1001) Google Scholar). H3K27me3, a silencing mark, is thought to be critical for establishment and maintenance of both constitutive and facultative heterochromatin, two chromatin structures that are strictly guarded within the cells since they dictate developmental and cell-type specificity for transcription, imprinting, X chromosome inactivation, and establishment of bivalent domains (Jin et al., 2011Jin C. Li J. Green C.D. Yu X. Han D. Xian B. Wang D. Huang X. Cao X. Yan Z. et al.Cell Met. 2011; 14 (this issue): 161-172Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar and references therein). They also suppress retrotransposal elements and protect the integrity of telomere- and centromere-proximal regions. H3K27me3 by the writer ESC-E(Z)/EED-EZH2 member of multisubunit complex PRC2, facilitates binding of the reader Polycomb (PC), a core component of the PRC1 complex. The latter complex compacts chromatin through an additional cascade of chromatin—specific modifications, such as monoubiquitylation of histone H2A. Loss of H3K27me3 occurs in cells from Hutchinson-Gilford progeria syndrome (HGPS) patients (Shumaker et al., 2006Shumaker D.K. Dechat T. Kohlmaier A. Adam S.A. Bozovsky M.R. Erdos M.R. Eriksson M. Goldman A.E. Khuon S. Collins F.S. et al.Proc. Natl. Acad. Sci. USA. 2006; 103: 8703-8708Crossref PubMed Scopus (560) Google Scholar), a rare and fatal human pathology resembling aspects of premature aging. Among other characteristics, HGPS cells exhibit severe nuclear-architecture defects marked by disorganization of the nuclear lamina and loss of heterochromatin (Burtner and Kennedy, 2010Burtner C.R. Kennedy B.K. Nat. Rev. Mol. Cell Biol. 2010; 11: 567-578Crossref PubMed Scopus (293) Google Scholar). The HGPS report findings prompted Jin et al., 2011Jin C. Li J. Green C.D. Yu X. Han D. Xian B. Wang D. Huang X. Cao X. Yan Z. et al.Cell Met. 2011; 14 (this issue): 161-172Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar to search for methyltransferases and demethylases that change in expression with age among human brain samples (Jin et al., 2011Jin C. Li J. Green C.D. Yu X. Han D. Xian B. Wang D. Huang X. Cao X. Yan Z. et al.Cell Met. 2011; 14 (this issue): 161-172Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar and references therein). One demethylase was found to rise in expression, prompting an examination of the C. elegans ortholog, utx-1. Strikingly, UTX-1 activity goes up as C. elegans age along with a concomitant decrease in H3K27me3. This is important to longevity since genetic approaches to reduce utx-1 expression confer a significant increase in life span. These worms are also more resistant to a variety of stress conditions linked to aging. Epistasis studies of utx-1 showed that reduced UTX-1 promotes life-span extension in a daf-16-dependent manner. Daf-16 encodes the FOXO transcription factor downstream of the insulin/IGF pathway, and its activity is required for life-span extension through reduced expression of the insulin IGF receptor, daf-2 (Kenyon, 2010Kenyon C. Ann. N Y Acad. Sci. 2010; 1204: 156-162Crossref PubMed Scopus (132) Google Scholar). What makes this report important is that Jin et al., 2011Jin C. Li J. Green C.D. Yu X. Han D. Xian B. Wang D. Huang X. Cao X. Yan Z. et al.Cell Met. 2011; 14 (this issue): 161-172Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar were able to work out a mechanism whereby increased UTX-1 activity and an associated loss of H3K27me3 lead to life-span extension. They show that loss of this histone PTM at the Igf1r/daf-2 gene, leading to enhanced transcription of daf-2 and elevated insulin signaling. This study therefore links altered epigenetic control with age to deregulation of the major signal transduction pathway (IIS) linked to aging. It also raises key questions, such as what events lead to enhanced UTX-1 activity. Altered H3K27me3 may be a signal of cellular stress with increased transcription of daf-2 being part of the response pathway. Identifying the molecular events that trigger this pathway may change our perspective on how altered insulin/IGF signaling contributes to the aging process. This study also suggests that a UTX-1-regulated chromatin signature might be evolutionarily conserved from invertebrates to mammals. The next challenge is to identify whether or not UTX-1-dependent H3K27me3 loss (1) impacts establishment and maintenance of facultative and constitutive heterochromatin, (2) promotes antagonistic to PcG-mediated silencing acetylation of H3K27, and (3) extends to neighboring nucleosomes or affects nucleosome positioning. Future investigations should also clarify whether an increase in UTX-1 activity leads to aging-related histone eviction (Feser et al., 2010Feser J. Truong D. Das C. Carson J.J. Kieft J. Harkness T. Tyler J.K. Mol. Cell. 2010; 39: 724-735Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar), recycling, and alterations in chromatin dynamics controlled by coordinated action of histone chaperones. Importantly, the experimental evidence presented by Jin et al., 2011Jin C. Li J. Green C.D. Yu X. Han D. Xian B. Wang D. Huang X. Cao X. Yan Z. et al.Cell Met. 2011; 14 (this issue): 161-172Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar suggests the possibility of ultimately slowing, or even reversing, aging through resetting epigenetic pathways that go awry as we get old. Reconstruction of the blueprints of molecular interactions between writers, erasers, readers, and the PTMs they create may permit the preservation of infrastructure of nuclear architecture. Such blueprints are in demand as researchers aim to realize the centuries long dream of finding a “fountain of youth” to enjoy old age largely free of disabilities. We apologize to our colleagues whose work we were unable to cite due to space constraints. Histone Demethylase UTX-1 Regulates C. elegans Life Span by Targeting the Insulin/IGF-1 Signaling PathwayJin et al.Cell MetabolismAugust 03, 2011In BriefEpigenetic modifications are thought to be important for gene expression changes during development and aging. However, besides the Sir2 histone deacetylase in somatic tissues and H3K4 trimethylation in germlines, there is scant evidence implicating epigenetic regulations in aging. The insulin/IGF-1 signaling (IIS) pathway is a major life span regulatory pathway. Here, we show that progressive increases in gene expression and loss of H3K27me3 on IIS components are due, at least in part, to increased activity of the H3K27 demethylase UTX-1 during aging. Full-Text PDF Open Archive
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