Silencing of Euchromatic Transposable Elements as a Consequence of Nuclear Lamina Dysfunction

Abstract

Transposable elements (TEs) are mobile genomic sequences that are normally repressed to avoid proliferation and genome instability. Gene silencing mechanisms repress TEs by RNA degradation or heterochromatin formation. Heterochromatin maintenance is therefore important to keep TEs silent. Loss of heterochromatic domains has been linked to lamin mutations, which have also been associated with derepression of TEs. In fact, lamins are structural components of the nuclear lamina (NL), which is considered a pivotal structure in the maintenance of heterochromatin domains at the nuclear periphery in a silent state. Here, we show that a lethal phenotype associated with Lamin loss-of-function mutations is influenced by Drosophila gypsy retrotransposons located in euchromatic regions, suggesting that NL dysfunction has also effects on active TEs located in euchromatic loci. In fact, expression analysis of different long terminal repeat (LTR) retrotransposons and of one non-LTR retrotransposon located near active genes shows that Lamin inactivation determines the silencing of euchromatic TEs. Furthermore, we show that the silencing effect on euchromatic TEs spreads to the neighboring genomic regions, with a repressive effect on nearby genes. We propose that NL dysfunction may have opposed regulatory effects on TEs that depend on their localization in active or repressed regions of the genome.Cells 2020, 9, 625 2 of 16 (PTGS) or to repress transcription by transcriptional gene silencing (TGS). TGS is achieved by formation of heterochromatin [5], and reduction of heterochromatin results in the activation of the transcriptionally repressed regions. A global loss of heterochromatin has been described during aging and is related to the derepression of TEs [6]. For this reason, it has been hypothesized that age-associated reduction of heterochromatin determines the loss of inactivation of TE expression and the consequent mobilization. It is known that heterochromatic regions tend to be associated with the nuclear lamina (NL), a structural scaffold lining the surface of the inner nuclear membrane [7]. NL is constituted by a network of intermediate filaments and has different functions including the chromatin anchorage [8]. Lamins are the major constituents of the NL and are classified into A-and B-type lamins [9]. In humans, the A-type lamins (i.e., lamin A and lamin C) are encoded by the LMNA gene, while the B-type lamins (i.e., lamin B1 and lamin B2) are encoded by the LMNB1 and LMNB2 genes, respectively. Lamin A and lamin C are produced by alternative splicing of a common primary transcript. In humans, mutations in LMNA or other nuclear lamina/envelope genes are responsible for a plethora of diseases termed laminopathies, which include muscular dystrophies, cardiomyopathy, lipodystrophies, and progeroid syndromes [10][11][12][13][14]. Two lamin genes are present in Drosophila, even if they cannot be classified in A-type or B-type lamins on the base of the homology sequence [15][16][17][18][19]. One of them, called Lamin (Lam) o...

Retrotransposons Down- and Up-Regulation in Aging Somatic Tissues

“…Food vials were changed every three days. The following strains were used: Canton S (wild type), flam A , w IR6RevII7 , Df(1)l11/FM7c B flam FM7 ; P{gypsy-lacZ.p12} [ 8 ] and flam BG02658 . Df(1)l11 deletion includes eor , flam , and wap genes [ 18 ].…”

“…This allows ZAM and Idefix expression in the follicular epithelium and in somatic tissues outside the ovary throughout Drosophila development (in embryos, larvae and adult flies) [ 7 ]. Permissive lines for gypsy mobilization have also been characterized, allowing gypsy activation in follicular cells and in the head tissues [ 8 , 9 , 10 ]. Regulation of TEs by flamenco involves the PIWI protein in the reproductive apparatus, and is PIWI independent in the somatic tissues, suggesting different molecular mechanisms of repression [ 7 ].…”

The Impact of Drosophila Awd/NME1/2 Levels on Notch and Wg Signaling Pathways

“…Three independent biological replicates were analyzed. Total RNA was extracted using TRI Reagent (Sigma-Merck, Darmstadt, Germany) RNA extraction protocol as described in [ 44 , 45 ]. RNA concentration and purity were estimated by measuring the absorbance at 260 nm and A260/A280 ratio.…”

The relationship of lamins with epigenetic factors during aging

“…Also, PLs are characterized by decrease in perinuclear heterochromatin and increase in cellular senescence -two conditions that correlate with dysregulation of TEs (Andrenacci et al, 2020). It can be assumed that in evolution, lamins arose as one of the protective mechanisms aimed at silencing TEs to protect hosts from genomic instability (Cavaliere et al, 2020). Therefore, laminopathies that cause premature aging and aging-associated pathology are most likely to cause activation of TEs as a key mechanism for the development of diseases (Andrenacci et al, 2020).…”

“…Silencing of TEs is normally ensured by the degradation of their RNA and the formation of heterochromatin. Therefore, TEs are characterized by activation during aging of organisms as a result of ageassociated deregulation of heterochromatin and microRNA (Cavaliere et al, 2020).…”