BMAL1 associates with chromosome ends to control rhythms in TERRA and telomeric heterochromatin

Park, Jinhee; Zhu, Qiaoqiao; Mirek, Emily T.; Na, Li; Raduwan, Hamidah; Anthony, Tracy G.; Belden, William J.

doi:10.1371/journal.pone.0223803

Cited by 14 publications

(9 citation statements)

References 55 publications

(58 reference statements)

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“… 80 In addition, a recent study suggests the involvement of BMAL1 in the regulation of telomeric heterochromatin. 81 Unlike BMAL1, which mainly maintains telomeric homeostasis, we found that CLOCK was enriched across diverse genomic repetitive sequences, including LINE1, satellite DNA, and rDNA, thus preventing aging-associated heterochromatin loss. Despite the different mechanisms, these studies collectively demonstrate the noncanonical roles of CLOCK and other core circadian proteins in regulating chromatin homeostasis.…”

Section: Discussionmentioning

confidence: 70%

Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration

et al. 2020

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Accumulating evidence indicates an association between the circadian clock and the aging process. However, it remains elusive whether the deregulation of circadian clock proteins underlies stem cell aging and whether they are targetable for the alleviation of aging-associated syndromes. Here, we identified a transcription factor-independent role of CLOCK, a core component of the molecular circadian clock machinery, in counteracting human mesenchymal stem cell (hMSC) decay. CLOCK expression was decreased during hMSC aging. In addition, CLOCK deficiency accelerated hMSC senescence, whereas the overexpression of CLOCK, even as a transcriptionally inactive form, rejuvenated physiologically and pathologically aged hMSCs. Mechanistic studies revealed that CLOCK formed complexes with nuclear lamina proteins and KAP1, thus maintaining heterochromatin architecture and stabilizing repetitive genomic sequences. Finally, gene therapy with lentiviral vectors encoding CLOCK promoted cartilage regeneration and attenuated age-related articular degeneration in mice. These findings demonstrate a noncanonical role of CLOCK in stabilizing heterochromatin, promoting tissue regeneration, and mitigating aging-associated chronic diseases.

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Section: Discussionmentioning

confidence: 70%

Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration

et al. 2020

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“…Similar outcomes of lifespan were obtained in Drosophila [77]. Park et al found that BMAL1 is associated with telomere length in zebrafish as well as mice; it is characterized by rhythmical binding to the ends of chromosomes, which may lead to the conclusion that the circadian clock components are greatly involved in telomere homeostasis regulation [78]. Moreover, the rhythms in the heterochromatin at the telomeres in zebrafish and mice support this hypothesis [78].…”

Section: Circadian Clock Disturbances and Accelerated Agingmentioning

confidence: 68%

“…Moreover, the rhythms in the heterochromatin at the telomeres in zebrafish and mice support this hypothesis [78]. Furthermore, BMAL1 probably takes part in the rhythmical epigenetics of telomeres and regulates the expression of a long non-coding RNA called telomeric repeat-containing RNA (TERRA), which is implicated in telomere protection by the recruitment of epigenetic factors [78]. BMAL1 -/mice are characterized by premature aging in cases of increased ROS production and cardiac telomere shortening.…”

Section: Circadian Clock Disturbances and Accelerated Agingmentioning

confidence: 99%

“…Park et al found that BMAL1 is associated with telomere length in zebrafish as well as mice; it is characterized by rhythmical binding to the ends of chromosomes, which may lead to the conclusion that the circadian clock components are greatly involved in telomere homeostasis regulation [78]. Moreover, the rhythms in the heterochromatin at the telomeres in zebrafish and mice support this hypothesis [78]. Furthermore, BMAL1 probably takes part in the rhythmical epigenetics of telomeres and regulates the expression of a long non-coding RNA called telomeric repeat-containing RNA (TERRA), which is implicated in telomere protection by the recruitment of epigenetic factors [78].…”

Section: Circadian Clock Disturbances and Accelerated Agingmentioning

confidence: 99%

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Obstructive Sleep Apnea as an Acceleration Trigger of Cellular Senescence Processes through Telomere Shortening

Turkiewicz

Ditmer

Sochal

et al. 2021

IJMS

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Obstructive sleep apnea (OSA) is chronic disorder which is characterized by recurrent pauses of breathing during sleep which leads to hypoxia and its two main pathological sequelae: oxidative stress and chronic inflammation. Both are also associated with cellular senescence. As OSA patients present with higher prevalence of age-related disorders, such as atrial hypertension or diabetes mellitus type 2, a relationship between OSA and accelerated aging is observable. Furthermore, it has been established that these OSA are associated with telomere shortening. This process in OSA is likely caused by increased oxidative DNA damage due to increased reactive oxygen species levels, DNA repair disruptions, hypoxia, chronic inflammation, and circadian clock disturbances. The aim of the review is to summarize study outcomes on changes in leukocyte telomere length (LTL) in OSA patients and describe possible molecular mechanisms which connect cellular senescence and the pathophysiology of OSA. The majority of OSA patients are characterized by LTL attrition due to oxidative stress, hypoxia and inflammation, which make a kind of positive feedback loop, and circadian clock disturbance.

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“…Subsequently, in another study using the zebrafish brain and the mice liver, a lncRNA Telomeric Repeat-containing RNA (TERRA) was found to be associated with circadian transcription factor BMAL1. Ablation of BMAL1 expression in a mouse model resulted in the disruption of TERRA's diurnal rhythmic expression and H3K9me3-mediated telomeric homeostasis, thus implicating, TERRA and BMAL-1 in aging-related telomeric erosion [108].…”

Section: Role Of Non-coding Rnas In Molecular Clock Regulation: Implimentioning

confidence: 96%

Role of Non-Coding RNAs in Lung Circadian Clock Related Diseases

Chinnapaiyan

Dutta

Devadoss

et al. 2020

IJMS

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Circadian oscillations are regulated at both central and peripheral levels to maintain physiological homeostasis. The central circadian clock consists of a central pacemaker in the suprachiasmatic nucleus that is entrained by light dark cycles and this, in turn, synchronizes the peripheral clock inherent in other organs. Circadian dysregulation has been attributed to dysregulation of peripheral clock and also associated with several diseases. Components of the molecular clock are disrupted in lung diseases like chronic obstructive pulmonary disease (COPD), asthma and IPF. Airway epithelial cells play an important role in temporally organizing magnitude of immune response, DNA damage response and acute airway inflammation. Non-coding RNAs play an important role in regulation of molecular clock and in turn are also regulated by clock components. Dysregulation of these non-coding RNAs have been shown to impact the expression of core clock genes as well as clock output genes in many organs. However, no studies have currently looked at the potential impact of these non-coding RNAs on lung molecular clock. This review focuses on the ways how these non-coding RNAs regulate and in turn are regulated by the lung molecular clock and its potential impact on lung diseases.

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BMAL1 associates with chromosome ends to control rhythms in TERRA and telomeric heterochromatin

Cited by 14 publications

References 55 publications

Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration

Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration

Obstructive Sleep Apnea as an Acceleration Trigger of Cellular Senescence Processes through Telomere Shortening

Role of Non-Coding RNAs in Lung Circadian Clock Related Diseases

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