Heterochromatin Mechanism

“Our study connects the dots between Werner syndrome and heterochromatin disorganization, outlining a molecular mechanism by which a genetic mutation leads to a general disruption of cellular processes by disrupting epigenetic regulation. More broadly, it suggests that accumulated alterations in the structure of heterochromatin may be a major underlying cause of cellular aging. This begs the question of whether we can reverse these alterations – like remodeling an old house or car – to prevent, or even reverse, age-related declines and diseases.”

A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging

dx.doi.org/10.1126/science.aaa1356

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PLoS Genet. 2012 Jan; 8(1): e1002473.

Published online 2012 Jan 26. doi:  10.1371/journal.pgen.1002473

PMCID: PMC3266895

PMID: 22291607

Heterochromatin Formation Promotes Longevity and Represses Ribosomal RNA Synthesis

Kimberly Larson,# 1 Shian-Jang Yan,# 1 , 2 Amy Tsurumi,# 1 Jacqueline Liu,# 1 Jun Zhou, 3 Kriti Gaur, 1 Dongdong Guo, 1 Thomas H. Eickbush, 3 and Willis X. Li 1 , 2 , *

Stuart K. Kim, Editor

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Abstract

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Organismal aging is influenced by a multitude of intrinsic and extrinsic factors, and heterochromatin loss has been proposed to be one of the causes of aging. However, the role of heterochromatin in animal aging has been controversial. Here we show that heterochromatin formation prolongs lifespan and controls ribosomal RNA synthesis in Drosophila. Animals with decreased heterochromatin levels exhibit a dramatic shortening of lifespan, whereas increasing heterochromatin prolongs lifespan. The changes in lifespan are associated with changes in muscle integrity. Furthermore, we show that heterochromatin levels decrease with normal aging and that heterochromatin formation is essential for silencing rRNA transcription. Loss of epigenetic silencing and loss of stability of the rDNA locus have previously been implicated in aging of yeast. Taken together, these results suggest that epigenetic preservation of genome stability, especially at the rDNA locus, and repression of unnecessary rRNA synthesis, might be an evolutionarily conserved mechanism for prolonging lifespan.

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Author Summary

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Aging is characterized by a progressive decline in vitality and tissue function, leading to the demise of the organism. Many models have been proposed to explain the aging phenomenon. Among the many competing and/or overlapping models is the heterochromatin loss model of aging, which posits that heterochromatin domains (which are set up early in embryogenesis) are gradually lost with aging, resulting in de-repression of silenced genes and aberrant gene expression patterns associated with old age. In this paper, we genetically tested the role of heterochromatin in Drosophila aging. We find that heterochromatin levels indeed affect animal lifespan and that heterochromatin represses, among other things, rRNA transcription. Loss of heterochromatin thus leads to an increase in rRNA transcription, a rate-limiting step in ribosome biogenesis and protein synthesis. We suggest that the biological functions of heterochromatin formation include controlling rRNA transcription, which might play an important role in general protein synthesis and animal longevity.

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Introduction

Organismal aging is accompanied by the accumulation of damage to DNA and other macromolecules, and a progressive decline in vitality and tissue function. The underlying mechanisms remain unclear, and many models have been proposed to explain the aging phenomenon. Prominent among these models is the “free radical theory of aging”, which posits that the gradual and collective damage done to biological macromolecules (including DNA and proteins) by reactive oxygen species (ROS) from intrinsic (e.g., metabolism) or extrinsic sources (e.g., radiation), is the major cause of organismal aging [1], [2]. Other competing (although some are overlapping) models of aging include genetically programmed senescence [3], [4], heterochromatin loss [5], telomere shortening [6], genomic instability [7], nutritional intake and growth signaling [8]–[10], to name a few. In the heterochromatin loss model of aging, Villeponteau (1997) has proposed that heterochromatin domains, which are set up early in embryogenesis, are gradually lost with aging, resulting in derepression of silenced genes and aberrant gene expression patterns associated with old age [5].

Experimental tests of the role of heterochromatin formation in animal aging, however, have produced controversial results [11]. On the one hand, cellular senescence is associated with an increase in localized heterochromatin formation in the form of Senescence-Associated Heterochromatin Foci (SAHFs), which are a hallmark of replicative senescence of aged cells in culture, and have also been found in the skin cells of aged animals [12]–[14]. On the other hand, it has been shown that premature aging diseases in human and animal models correlate with global heterochromatin loss [15]–[17].

Heterochromatin is important for chromosomal packaging and segregation, and is thus important for genome stability [18], [19]. Indeed, it has been shown in Drosophila th

RESEARCH HETEROCHROMATIN BOOST

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Heterochromatin

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Heterochromatin is a tightly packed form of DNA or condensed DNA, which comes in multiple varieties. These varieties lie on a continuum between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role in the expression of genes. Because it is tightly packed, it was thought to be inaccessible to polymerases and therefore not transcribed, however according to Volpe et al. (2002),[1] and many other papers since,[2] much of this DNA is in fact transcribed, but it is continuously turned over via RNA-induced transcriptional silencing (RITS). Recent studies with electron microscopy and OsO4 staining reveal that the dense packing is not due to the chromatin.[3]

Constitutive heterochromatin can affect the genes near itself (position-effect variegation). It is usually repetitive and forms structural functions such as centromeres or telomeres, in addition to acting as an attractor for other gene-expression or repression signals.

Facultative heterochromatin is the result of genes that are silenced through a mechanism such as histone deacetylation or Piwi-interacting RNA (piRNA) through RNAi. It is not repetitive and shares the compact structure of constitutive heterochromatin. However, under specific developmental or environmental signaling cues, it can lose its condensed structure and become transcriptionally active.[4]

Heterochromatin has been associated with the di- and tri-methylation of H3K9 in certain portions of the genome.[5]

pastedGraphic.png

The nucleus of a human cell showing the location of heterochromatin

Note that the informal diagram shown here may be in error as to the location of heterochromatin. An inactivated X-chromosome (a.k.a. Barr body) migrates to the nuclear membrane alone, leaving the active X and other chromosomes within the nucleoplasm (away from the membrane in general). Other heterochromatin appear as particles separate from the membrane, “Heterochromatin appears as small, darkly staining, irregular particles scattered throughout the nucleus …”.[6]

References[edit]

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Volpe, Thomas A.; Kidner, Catherine; Hall, Ira M.; Teng, Grace; Grewal, Shiv I. S.; Martienssen, Robert A. (2002-09-13). “Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi”. Science. 297 (5588): 1833–1837. doi:10.1126/science.1074973. ISSN 1095-9203. PMID 12193640.

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“What is the current evidence showing active transcription withinin…” www.researchgate.net. Retrieved 2016-04-30.

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Ou, Horng D.; Phan, Sébastien; Deerinck, Thomas J.; Thor, Andrea; Ellisman, Mark H.; O’Shea, Clodagh C. (2017-07-28). “ChromEMT: Visualizing 3D chromatin structure and compaction in interphase and mitotic cells”. Science. 357 (6349): eaag0025. doi:10.1126/science.aag0025. ISSN 0036-8075. PMC 5646685pastedGraphic_1.png. PMID 28751582.

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Oberdoerffer, P; Sinclair, D (2007). “The role of nuclear architecture in genomic instability and ageing”. Nature Reviews Molecular Cell Biology. 8: 692–702. doi:10.1038/nrm2238.

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Rosenfeld, Jeffrey A; Wang, Zhibin; Schones, Dustin; Zhao, Keji; Desalle, Rob; Zhang, Michael Q (31 March 2009). “Determination of enriched histone modifications in non-genic portions of the human genome”. BMC Genomics. 10 (1): 143. doi:10.1186/1471-2164-10-143. PMC 2667539pastedGraphic_1.png. PMID 19335899.

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Shown here: Electron microscope image of nucleus with heterochromatin particles annotated [1]

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Elgin, S.C. (1996). “Heterochromatin and gene regulation in Drosophila“. Current Opinion in Genetics & Development. 6 (2): 193–202. doi:10.1016/S0959-437X(96)80050-5. ISSN 0959-437X.

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