Periphilin is strongly expressed in the murine nervous system and is indispensable for murine development

Soehn, Anne S.; Pham, Thu-Trang; Schaeferhoff, Karin; Floss, Thomas; Weisenhorn, Daniela M. Vogt; Wurst, Wolfgang; Bonin, Michael; Rieß, Olaf

doi:10.1002/dvg.20553

Cited by 12 publications

(10 citation statements)

References 22 publications

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“…The recently-identified HUSH complex is an important regulator of mammalian heterochromatin that is critical for silencing of newly-integrated retroviruses9 and for normal embryonic development12,13. Here, through a genome-wide CRISPR/Cas9-mediated forward genetic screen, we have identified MORC2 as an additional accessory member of the HUSH complex.…”

Section: Discussionmentioning

confidence: 96%

“…HUSH-mediated recruitment of the methyltransferase SETDB1 to these sites results in the ‘writing’ of additional H3K9me3, thereby mediating the spreading of heterochromatin across incoming transgenes9. The HUSH complex also plays a critical role in endogenous heterochromatin maintenance, as deletion of HUSH subunits results in decreased H3K9me3 at hundreds of genomic loci9 and early embryonic lethality in the mouse12,13.…”

Section: Introductionmentioning

confidence: 99%

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Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2

Timms²,

et al. 2017

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Dominant mutations in the MORC2 gene have recently been shown to cause axonal Charcot-Marie-Tooth (CMT) disease, but the cellular function of MORC2 is poorly understood. Here, through a genome-wide CRISPR/Cas9-mediated forward genetic screen, we identify MORC2 as an essential gene required for epigenetic silencing by the HUSH complex. HUSH recruits MORC2 to target sites in heterochromatin. We exploit a new method – Differential Viral Accessibility (DIVA) – to show that loss of MORC2 results in chromatin decompaction at these target loci, which is concomitant with a loss of H3K9me3 deposition and transcriptional derepression. The ATPase activity of MORC2 is critical for HUSH-mediated silencing, and the most common mutation affecting the ATPase domain found in CMT patients (R252W) hyper-activates HUSH-mediated repression in neuronal cells. These data define a critical role for MORC2 in epigenetic silencing by the HUSH complex and provide a mechanistic basis underpinning the role of MORC2 mutations in CMT disease.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2

Timms²,

et al. 2017

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“…This raises another question, why has the HUSH complex evolved more recently? Although further work will be required to understand why this might be, it is clear that HUSH plays a critical role in higher organisms, as both TASOR and Periphilin are indispensable for murine development. Loss of HUSH subunits results in decreased H3K9me3 at hundreds of genomic loci , and so the HUSH complex may, therefore, have an essential role in heterochromatin maintenance in the early embryo, or may play a critical role in directing normal gene expression programs during early development.…”

Section: How Has the Hush Complex Evolved?mentioning

confidence: 99%

Position‐effect variegation revisited: HUSHing up heterochromatin in human cells

2016

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Much of what we understand about heterochromatin formation in mammals has been extrapolated from forward genetic screens for modifiers of position-effect variegation (PEV) in the fruit fly Drosophila melanogaster. The recent identification of the HUSH (Human Silencing Hub) complex suggests that more recent evolutionary developments contribute to the mechanisms underlying PEV in human cells. Although HUSH-mediated repression also involves heterochromatin spreading through the reading and writing of the repressive H3K9me3 histone modification, clear orthologues of HUSH subunits are not found in Drosophila but are conserved in vertebrates. Here we compare the insights into the mechanisms of PEV derived from genetic screens in the fly, the mouse and in human cells, review what is currently known about the HUSH complex and discuss the implications of HUSH-mediated silencing for viral latency. Future studies will provide mechanistic insight into HUSH complex function and reveal the relationship between HUSH and other epigenetic silencing complexes.

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“…Periphilin is indispensable for development. In mice, homozygous deficiency of Periphilin is lethal early in embryogenesis and heterozygous deficiency is compensated by increased expression from the wild-type allele (Soehn et al, 2009). Overexpression of Periphilin transcriptionally represses certain proteins causing cell cycle arrest (Kurita et al, 2007;Kurita et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Periphilin self-association underpins epigenetic silencing by the HUSH complex

Prigozhin

Albecka

Douse

et al. 2019

Preprint

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Transcription of integrated DNA from viruses or transposable elements is tightly regulated to prevent pathogenesis. The Human Silencing Hub (HUSH), composed of Periphilin, TASOR and MPP8, silences transcriptionally active viral and endogenous transgenes. HUSH recruits effectors that alter the epigenetic landscape and chromatin structure, but how HUSH recognizes target loci and represses their expression remains unclear. We identify the physicochemical properties of Periphilin necessary for HUSH assembly and silencing. A disordered N-terminal domain (NTD) and structured C-terminal domain are essential for silencing. A crystal structure of the Periphilin-TASOR core complex shows Periphilin forms a-helical homodimers, which each bind a single TASOR molecule. The NTD binds RNA non-specifically and forms insoluble aggregates through an arginine/tyrosine-rich sequence reminiscent of low-complexity regions from self-associating RNA-binding proteins. Residues required for TASOR binding and aggregation were required for HUSH-dependent silencing and genome-wide deposition of repressive mark H3K9me3. The NTD was functionally complemented by low-complexity regions from certain RNA-binding proteins and proteins that form condensates or fibrils. Our work suggests the associative properties of Periphilin promote HUSH aggregation on nascent transcripts. Running title: Function of Periphilin in HUSH silencingKeywords: Transcriptional repression; epigenetic silencing; histone H3 lysine 9 methylation (H3K9me3); transposable element (TE); long interspersed nuclear element-1 (LINE-1); lowcomplexity sequence; disordered region; arginine/tyrosine-rich region; biomolecular condensate; liquid phase separation; membraneless compartment; RNA-binding protein syncytiotrophoblast fusion in placental development (Dupressoir et al, 2012;Friedli & Trono, 2015).A subset of TEs can autonomously replicate through an RNA intermediate and reintegrate into the genome like retroviruses. Some of these TEs are endogenous retrovirus (ERV) genomes inherited from ancestral infections of germline. The other type of autonomously replicating TE in humans are the non-viral LINE-1 (long interspersed nuclear element-1) retroelements. Active ERVs and LINE-1s are transcribed and encode reverse transcriptase and integrase enzymes,

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Periphilin is strongly expressed in the murine nervous system and is indispensable for murine development

Cited by 12 publications

References 22 publications

Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2

Hyperactivation of HUSH complex function by Charcot–Marie–Tooth disease mutation in MORC2

Position‐effect variegation revisited: HUSHing up heterochromatin in human cells

Periphilin self-association underpins epigenetic silencing by the HUSH complex

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