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Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro B cells

ABSTRACT: The establishment of distinct transcription programs during development is controlled by transcription factor networks acting in specific chromatin environments. The H3K9me3-specific histone methyltransferase Setdb1 impacts on transcriptional regulation by repressing both developmental genes and retrotransposons. How impaired retrotransposon silencing may lead to developmental phenotypes is currently unclear. Here we show that loss of Setdb1 in pro-B cells completely abrogates B cell development. In pro-B cells, Setdb1 is dispensable for silencing of lineage-inappropriate developmental genes. Instead, we detect strong derepression of endogenous Murine Leukemia Virus (MLV) copies. Production of MLV proteins leads to activation of the unfolded protein response pathway and apoptosis. Thus, our data demonstrate that B cell development critically depends on the proper repression of retrotransposon sequences through Setdb1.

ORGANISM(S): Mus musculus

PROVIDER: GSE77636 | GEO | 2016/07/20

SECONDARY ACCESSION(S): PRJNA311085

REPOSITORIES: GEO

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Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro B cells

Project description:The establishment of distinct transcription programs during development is controlled by transcription factor networks acting in specific chromatin environments. The H3K9me3-specific histone methyltransferase Setdb1 impacts on transcriptional regulation by repressing both developmental genes and retrotransposons. How impaired retrotransposon silencing may lead to developmental phenotypes is currently unclear. Here we show that loss of Setdb1 in pro-B cells completely abrogates B cell development. In pro-B cells, Setdb1 is dispensable for silencing of lineage-inappropriate developmental genes. Instead, we detect strong derepression of endogenous Murine Leukemia Virus (MLV) copies. Production of MLV proteins leads to activation of the unfolded protein response pathway and apoptosis. Thus, our data demonstrate that B cell development critically depends on the proper repression of retrotransposon sequences through Setdb1. Transcriptomic and chromatin analysis of control and Setdb1-deficient pro-B cells

2016-07-20 | E-GEOD-77636 | biostudies-arrayexpress

NEURON-SPECIFIC CHROMOSOMAL MEGADOMAIN ORGANIZATION IS ADAPTIVE TO RECENT RETROTRANSPOSON EXPANSIONS

Project description:Here, we mapped cell-type specific chromatin domain organization in adult mouse cerebral cortex and report strong enrichment of Endogenous Retrovirus 2 (ERV2) repeat sequences in the neuron-specific heterochromatic 'B2NeuN+' megabase-scaling subcompartment. Comparative chromosomal conformation mapping in Mus spretus and Mus musculus revealed neuron-specific reconfigurations tracking recent ERV2 retrotransposon expansions in the murine germline, with significantly higher B2 megadomain contact frequencies at sites with ongoing ERV2 insertions in Mus musculus. Ablation of the retrotransposon silencer Kmt1e/Setdb1 (KO) triggered B2 megadomain disintegration and rewiring with open chromatin domains enriched for cellular stress response genes, along with severe neuroinflammation and proviral assembly of ERV2/Intracisternal-A-Particles (IAPs) infiltrating dendrites and spines. We conclude that neuronal megadomain architectures include evolutionarily adaptive heterochromatic organization which, upon perturbation, unleashes ERV proviruses with strong tropism within mature neurons.

2021-10-11 | GSE168524 | GEO

Impaired function of rDNA transcription initiation machinery leads to derepression of ribosomal genes with insertions of R2 retrotransposon

Project description:Eukaryotic genomes harbor hundreds of rRNA genes, many of which are transcriptionally silent. However, little is known about selective regulation of individual rDNA units. In Drosophila melanogaster, some rDNA repeats contain insertions of the R2 retrotransposon, which is capable to be transcribed only as part of pre-rRNA molecules. rDNA units with R2 insertions are usually inactivated, although R2 expression may be beneficial in cells with decreased rDNA copy number. Here we found that R2-inserted rDNA units are enriched with HP1a and H3K9me3 repressive mark, whereas disruption of the heterochromatin components slightly affects their silencing in ovarian germ cells. Surprisingly, we observed a dramatic upregulation of R2-inserted rRNA genes in ovaries lacking Udd (Under-developed) or other subunits (TAF1b and ТAF1c-like) of the SL1-like complex, which is homologues to mammalian Selective factor 1 (SL1) involved in rDNA transcription initiation. Derepression of rRNA genes with R2 insertions was accompanied by a reduction of H3K9me3 and HP1a enrichment. We suggest that the impairment of the SL1-like complex affects a mechanism of selective activation of intact rDNA units which competes with heterochromatin formation. We also propose that R2 derepression may serve as an adaptive response to compromised rRNA synthesis.

2021-10-09 | GSE183035 | GEO

Reconstructing de novo silencing of an active plant retrotransposon: dynamics, mechanisms, biological implications

Project description:In plants, maintenance-methylation mediated by METHYLTRANSFERASE-1 (MET1), siRNA-directed de-novo methylation, and chromatin remodeling by DECREASE IN DNA METHYLATION -1 (DDM1) promote transcriptional gene-silencing of transposable elements (TEs). This process is mostly investigated at steady states reflecting how long-established silent conditions are maintained, faithfully re-iterated or temporarily modified during growth, stress and over generations. How invasive TEs are detected and silenced de novo, however, remains largely unknown. Using inbred lineages of hybrid Arabidopsis epigenomes combining wild-type and met1 or ddm1 chromosomes, we have deciphered the timing, spatial distribution and mechanisms underpinning the proliferation and eventual demise of the endogenous retrotransposon évadé (EVD). Both developmental and molecular features of EVD biology, including a remarkable ability to evade RNA interference, ultimately contribute to its silencing over multiple generations. The underlying processes are accompanied by widespread diversification of the Arabidopsis genome and de-novo epiallelism creating an extensive reservoir of selectable and potentially adaptive traits. Differential expression of EVADE small RNAs between three generations of one specific Col0 met1 derived EpiRIL.

2013-07-02 | E-GEOD-43412 | biostudies-arrayexpress

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Project description:Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several pathogenic mutations have been identified, the vast majority of ALS cases have no family history of disease. Thus, for most ALS cases, the disease may be a product of multiple pathways contributing to varying degrees in each patient. Using machine learning algorithms, we stratified the transcriptomes of 148 ALS postmortem cortex samples into three distinct molecular subtypes. The largest cluster, identified in 61% of patient samples, displayed hallmarks of oxidative and proteotoxic stress. Another 19% of the samples showed predominant signatures of glial activation. Finally, a third group (20%) exhibited high levels of retrotransposon expression and signatures of TARDBP/TDP-43 dysfunction. We further demonstrated that TDP-43 (1) directly binds a subset of retrotransposon transcripts and contributes to their silencing in vitro, and (2) pathological TDP-43 aggregation correlates with retrotransposon de-silencing in vivo.

2019-10-04 | GSE124439 | GEO

Histone chaperone CAF-1 is essential for retrotransposon silencing by mediating histone H4K20me3 deposition in mouse preimplantation embryos

Project description:Retrotransposons are widely spread in the mammalian genome and are usually silenced during development to avoid transposition-inducing mutations. But how they are repressed in embryos shortly before implantation remain to be identified, since the genome at this stage is globally hypomethylated. Here we show a histone chaperon, CAF-1, is responsible for retrotransposon silencing at the morula-blastocyst stages by depositing histone H4 lysine 20 trimethylation (H4K20me3). Knockdown of CAF-1 with a specific siRNA resulted in derepression of LINE-1, SINE-B2 and IAP associated with the decreased H4K20me3 level, and arrested embryonic development at the morula stage. The identical results were obtained with siRNAs against Suv420h1/2, H4K20 methyltransferases. Treatment with reverse transcriptase inhibitors rescued at least a part of these embryos. Thus, CAF-1 ensures the genomic integrity of preimplantation embryos by establishing repressive histone marks in the multiple retrotransposon classes. Comparative gene expression analyses using P150 knockdown (P150KD) embryos at morula stage were performed by microarray. P150KD embryos were produced with the injection of P150 siRNA into 1-cell embryos. As controls, siControl embryos were produced by the injection of control siRNA. These embryos were subjected to gene expression microarray.

2015-11-01 | E-GEOD-69260 | biostudies-arrayexpress

Maternally deposited germline piRNAs silence the tirant retrotransposon in somatic cells

Project description:Transposable elements (TEs), whose propagation can result in severe damage to the host genome, are silenced in the animal gonad by Piwi-interacting RNAs (piRNAs). piRNAs produced in the ovaries are deposited in the embryonic germline and initiate TE repression in the germline progeny. Whether the maternally transmitted piRNAs play a role in the silencing of somatic TEs is, however, unknown. Here we show that maternally transmitted piRNAs from the tirant retrotransposon in Drosophila are required for the somatic silencing of the TE and correlate with an increase in histone H3K9 trimethylation an active tirant copy. Comparison of tirant piRNAs in two Drosophila simulans natural populations.

2013-04-09 | E-GEOD-40592 | biostudies-arrayexpress

Histone chaperone CAF-1 is essential for retrotransposon silencing by mediating histone H4K20me3 deposition in mouse preimplantation embryos

2015-11-01 | GSE69260 | GEO

UBQLN2 restrains the domesticated retrotransposon PEG10 to maintain neuronal health in ALS

Project description:Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease characterized by motor neuron dysfunction and loss, leading to progressive paralysis and death. A portion of ALS cases is caused by mutation of the proteasome shuttle factor Ubiquilin 2 (UBQLN2), but the molecular pathway leading from UBQLN2 dysfunction to neurodegenerative disease remains unclear. Here, we demonstrate a major function of UBQLN2 in regulating activity of the domesticated gag-pol retrotransposon ‘paternally expressed gene 10’ (PEG10) in human cells and tissues. UBQLN2 exclusively facilitates degradation of the frameshifted gag-pol form of PEG10 through recognition of a unique polyproline repeat. In cells, the PEG10 gag-pol protein cleaves itself in a mechanism reminiscent of retrotransposon self-processing to generate a liberated ‘nucleocapsid’ fragment, which uniquely localizes to the nucleus. Overexpression of the nucleocapsid fragment upregulates transcription of neuronal genes involved in axon remodeling, which were also affected in sporadic ALS (sALS) patient tissues. Finally, proteomics of spinal cords from ALS patients revealed that PEG10 gag-pol is significantly elevated in disease compared to healthy controls. These findings implicate the retrotransposon-like activity of PEG10 as a contributing mechanism in ALS through regulation of neuronal gene expression, and restraint of PEG10 as a primary function of UBQLN2.

2023-03-24 | PXD031964 | Pride

LTR-retrotransposon control by tRNA-derived small RNA

Project description:Transposon reactivation is an inherent danger in cells that lose epigenetic silencing during developmental reprogramming. In the mouse, LTR-retrotransposons, or endogenous retroviruses (ERV), account for most novel insertions and are expressed in the absence of histone H3 Lysine 9 trimethylation in preimplantation stem cells. We found abundant, 18 nt tRNA-derived small RNA (tRF) in these cells, and ubiquitously expressed 22 nt tRFs, that include the 3' terminal CCA of mature tRNAs, and target the tRNA primer binding site (PBS) essential for ERV reverse transcription. We show that the two most active ERV families, IAP and MusD/ETn, are major targets and are strongly inhibited by tRFs in retrotransposition assays. 22 nt tRFs post-transcriptionally silence coding-competent ERVs, while 18 nt tRFs specifically interfere with reverse transcription and retrotransposon mobility. The PBS offers a unique target to specifically inhibit LTR-retrotransposons and tRF-targeting is a potentially highly conserved mechanism of small RNA-mediated transposon control.

2017-06-29 | GSE82199 | GEO

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