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SIRT7 tethering of L1 elements to the nuclear lamina mediates their transcriptional repression

ABSTRACT: Long interspersed elements-1 (LINE-1, L1) are retrotransposons that hold the capacity of selfpropagation in the genome with potential mutagenic outcomes. How somatic cells restrict L1 activity and how this process becomes dysfunctional during aging and in cancer cells is poorly understood. L1s are enriched at lamin associated domains, heterochromatic regions of the nuclear periphery. Whether this association is necessary for their repression has been elusive. Here we show that the sirtuin family member SIRT7 participates in the epigenetic transcriptional repression of L1 genome-wide in both mouse and human cells. SIRT7 depletion leads to increased L1 expression and retrotransposition. Mechanistically, we identify a novel interplay between SIRT7 and Lamin A/C in L1 repression. Our results demonstrate that SIRT7-mediated H3K18 deacetylation regulates L1 expression by promoting L1 association with elements of the nuclear lamina. The failure of such activity might contribute to the observed genome instability and compromised viability in SIRT7 knockout mice. Overall, our results reveal a novel function of SIRT7 on chromatin organization by mediating the anchoring of L1 to the nuclear envelope, and a new mechanism by which the nuclear lamina maintains genome integrity.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE106964 | GEO | 2019/06/03

REPOSITORIES: GEO

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SIRT7 tethering of L1 elements to the nuclear lamina mediates their transcriptional repression

Project description:SIRT7 tethering of L1 elements to the nuclear lamina mediates their transcriptional repression

| PRJNA418599 | ENA

Inducible repositioning of mouse gene tethering to the inner nuclear membrane

Project description:Nuclear compartmentalization appears to play an important role in regulating metazoan genes. While studies on immunoglobulin (Ig) and other loci have correlated positioning at the nuclear lamina with gene repression, the functional consequences of this compartmentalization remain untested. We devised an approach for inducible tethering of genes to the inner nuclear membrane (INM) and demonstrate with 3D DNA-ImmunoFISH, repositioning of chromosomal regions to the nuclear lamina. Relocalization requires mitotic nuclear envelope breakdown and reformation. Tethering leads to the accumulation of lamin and INM proteins but not to association with pericentromeric heterochromatin or nuclear pore complexes. Recruitment of genes to the INM can result in their transcriptional repression. Using DamID we show that as is the case for our model system, inactive Ig loci at the nuclear periphery are contacted by INM and lamina components. We propose that such molecular interactions are used to compartmentalize and limit the accessibility of Ig loci. Experiment Overall Design: We used microarray to analyze the transcription status of genomic regions are inducibly tethered to the INM

2008-06-11 | E-GEOD-10176 | biostudies-arrayexpress

SIRT7 is a histone H3 lysine 18 deacetylase that regulates oncogenic transformation

Project description:Sirtuin proteins regulate diverse cellular pathways that influence genomic stability, metabolism, and ageing. SIRT7 is a mammalian sirtuin whose biochemical activity, molecular targets, and physiologic functions have been unclear. Here we show that SIRT7 is an NAD+-dependent, histone H3 acetyl-lysine 18 (H3K18Ac) deacetylase that stabilizes the transformed state of cancer cells. Genome-wide binding studies reveal that SIRT7 binds to promoters of a specific set of gene targets, where it deacetylates H3K18Ac and promotes transcriptional repression. The spectrum of SIRT7 target genes is defined in part by interaction of SIRT7 with the cancer-related ETS transcription factor ELK4, and comprises numerous genes with links to tumour suppression. Notably, selective hypoacetylation of H3K18Ac has recently been linked to oncogenic transformation, and in patients, is associated with aggressive tumour phenotypes and poor prognosis. We find that deacetylation of H3K18Ac by SIRT7 is necessary for maintaining essential features of human cancer cells including anchorage independent growth and escape from contact inhibition. Moreover, SIRT7 is necessary for a global hypoacetylation of H3K18Ac associated with cellular transformation by viral oncoproteins. Finally, SIRT7 depletion markedly reduces the tumourigenicity of human cancer cell xenografts in mice. Together, our work establishes SIRT7 as the first known site-specific H3K18Ac deacetylase and demonstrates a pivotal role for SIRT7 in chromatin regulation, cellular transformation programs, and tumour formation in vivo. SIRT7 ChIP-seq was performed in K562 cell lines under normal conditions. Two replicates were performed for both the SIRT7 ChIP as well as input control.

2012-05-06 | E-GEOD-28149 | biostudies-arrayexpress

SIRT7 counteracts mesenchymal stem cell senescence via stabilizing heterochromatin

Project description:Human mesenchymal stem cell (hMSC) senescence contributes to the imbalance of tissue homeostasis during aging. However, the connection between Sirtuin 7 (SIRT7) and hMSC homeostasis remains unclear. Here, we discovered a pivotal role of SIRT7 in protecting hMSC from senescence. We detected a decreased expression of SIRT7 during hMSC aging, while overexpression of which reversed premature hMSC senescence phenotypes. Mechanistically, we proved SIRT7 as a novel interacting protein of the heterochromatin complex, whose deficiency disrupted heterochromatin organization, thereby contributing to the derepression of the retrotransposon Long Interspersed Element 1 (LINE1 or L1). SIRT7-deficient hMSCs accumulated LINE1 in cytoplasm stimulating innate immune response by activated the cyclic GMP-AMP synthase (cGAS) and its downstream signaling effector stimulator of interferon genes (STING). Moreover, reverse-transcriptase inhibitors (RTis), such as Lamivudine (3TC), attenuated these senescence phenotypes of SIRT7-deficient hMSCs. Taken together, our findings identify SIRT7-heterochromatin via LINE1-cGAS/STING influence innate immune response, which contributes more comprehensive understanding of the physiological and function of SIRT7 and help us to find novel targets for the treatment of aging and aging relative diseases.

2020-06-29 | GSE146247 | GEO

SIRT7 suppresses tumorigenesis by attenuating MYC activity

Project description:SIRT7 is a member of the mammalian sirtuin family of NAD+ dependent deacylases, and interacts with RNA polymerase I and UBF to regulate rDNA transcription. Various studies in mammalian cells and human clinical data have linked SIRT7 to cancer. However studies differ as to whether SIRT7 is oncogenic or tumor suppressive. Here we analyzed SIRT7 knockout mice and found SIRT7 deficiency caused sub-Mendelian birth numbers and a reduction in body size. Moreover, at 18 month of age, roughly 60 % of the SIRT7 knockout mice develop hepatocellular carcinoma (HCC), in many cases leading to suspected metastasis. Several HCC associated genes were up-regulated in livers of mice as young as 6 months of age, particularly targets of the proto-oncogene, c- MYC. Indeed SIRT7 interacts with MYC at endogenous protein levels and also represses MYC activity. Our findings thus show that SIRT7 acts as a tumor suppressor in vivo, and may suggest novel strategies to treat liver cancer. The mRNAs from 3 replicates of mouse Wildtype liver compared to 3 replicates of mouse liver lacking SIRT7

2014-08-20 | E-GEOD-50076 | biostudies-arrayexpress

SIRT7 is a histone H3 lysine 18 deacetylase that regulates oncogenic transformation

2012-05-07 | GSE28149 | GEO

LINE-1 RNA is causative of heterochromatin erosion and target for amelioration of senescent phenotypes in progeroid syndromes

Project description:Constitutive heterochromatin is responsible for genome repression of DNA enriched in repetitive sequences, telomeres, and centromeres. In higher eukaryotes, constitutive heterochromatin is mostly segregated at the nuclear periphery, where the interaction with the nuclear lamina makes the genome more resistant to transcription. During physiological and pathological premature aging, heterochromatin homeostasis is profoundly compromised. Here we show that LINE-1 (L1) RNA accumulation is an early event in both typical and atypical progeroid syndromes. Depletion of L1 RNA in cells from different progeroid syndrome patients using specific antisense oligonucleotides (ASO) restores the levels of heterochromatin epigenetic marks, reverses DNA methylation age and counteracts the expression of senescence-associated genes. Moreover, proteome profiling involved in senescence phenotype was partially restored upon depletion of LINE-1 RNA in both Hutchinson-Gilford Progeria Syndrome (HGPS) and Werner syndrome (WRN-/-).

2022-11-02 | PXD032944 | Pride

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver.

Project description:Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age-dependent metabolic changes, but the mechanism is unknown. Here we profile lamina-associated domains (LADs) using lamin B1 ChIP-Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1-associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24-deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de-repression of PPAR and LXR-dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de-repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis.

2018-01-19 | GSE78177 | GEO

Lamin A acetylation shapes nuclear architecture and safeguards genomic integrity

Project description:The nuclear lamina constitutes more than a structural scaffold for the nucleus and plays a crucial role in protection of genomic integrity. Here we report that the loss of the lysine acetyl-transferase (KAT) MOF leads to nuclear architecture defects during interphase including micronuclei formation. We identify Lamin A/C, a major component of the nuclear lamina, to be an acetylation target of MOF. A point mutation in Lamin A phenocopies nuclear morphology defects observed upon Mof-deletion. Through single cell DNA sequencing, we reveal that either loss of Mof or Lamin A mutation result in extensive genomic instability, including chromothripsis. Our work establishes MOF-dependent Lamin acetylation as a key regulator of nuclear architecture maintenance in mammals.

2019-08-16 | PXD008539 | Pride

SIRT7-dependent deacetylation of the U3-55k protein controls pre-rRNA processing [CLIP-Seq]

Project description:SIRT7 is an NAD+-dependent protein deacetylase with important roles in ribosome biogenesis and cell proliferation. Previous studies have established that SIRT7 is associated with RNA polymerase I, interacts with pre-rRNA and promotes rRNA synthesis. Here we show that SIRT7 is also associated with snoRNAs that are involved in pre-rRNA processing and rRNA maturation. Knockdown of SIRT7 impairs U3 snoRNA-dependent early cleavage steps that are necessary for generation of 18S rRNA. Mechanistically, SIRT7 deacetylates U3-55k, a core component of the U3 snoRNP complex, and reversible acetylation of U3-55k modulates the association of U3-55k with U3 snoRNA. Deacetylation by SIRT7 enhances U3-55k binding to U3 snoRNA, which is a prerequisite for pre-rRNA processing. Under stress conditions, SIRT7 is released from nucleoli, leading to hyperacetylation of U3-55k and attenuation of prerRNA processing. The results reveal a multifaceted role of SIRT7 in ribosome biogenesis, regulating both transcription and processing of rRNA. CLIP-seq was performed in Flag-SIRT7-293T cells.

2016-01-07 | E-GEOD-76578 | biostudies-arrayexpress

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