Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s

ABSTRACT: The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We found that depletion of HUSH components in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect was mainly attributed to MDA5 and RIG-I sensing of double-stranded RNAs and coincided with upregulated LINE-1 RNAs. This included the human-specific family, L1HS, which produced bidirectional RNAs of around 6Kb, as well as ancient primate-conserved LINE-1s. LTRs nearby ISGs were derepressed likely rendering these genes more responsive to interferon. LINE-1 shRNAs could abrogate the HUSH-dependent response, while overexpression of an engineered LINE-1 construct could activate interferon signaling. Finally, we found that the HUSH component, MPP8 is frequently downregulated in diverse cancers and that its depletion leads to DNA damage. These results suggest that LINE-1s may drive physiological or autoinflammatory responses through RNA sensing and gene-regulatory roles and are controlled by the HUSH complex.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135765 | GEO | 2020/09/28

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression

Project description:Transposable elements (TEs) are widespread genetic parasites known to be kept under tight transcriptional control. Here, we describe a functional connection between the mouse-orthologous ‘nuclear exosome targeting (NEXT)’ and ‘human silencing hub (HUSH)’ complexes, involved in nuclear RNA decay and the epigenetic silencing of TEs, respectively. Knocking out the NEXT component ZCCHC8 in embryonic stem cells results in elevated TE RNA levels. We identify a physical interaction between ZCCHC8 and the MPP8 protein of HUSH and establish that HUSH recruits NEXT to chromatin at TE loci. However, while NEXT and HUSH both dampen TE RNA expression, their activities predominantly affect shorter non-polyadenylated and full-length polyadenylated transcripts, respectively. Indeed, our data suggest that the repressive action of HUSH promotes a condition, favouring NEXT RNA decay activity. In this way, transcriptional and post-transcriptional machineries synergise to suppress the genotoxic potential of TE RNAs.

2022-03-28 | GSE178550 | GEO

RNA-seq analysis of transcriptomic changes in WT and MPHOSPH8 KO MOLM-13 leukemia cells

Project description:Human cancers including acute myeloid leukemia (AML) hijack epigenetic machinery to drive malignant self-renewal, whereas dysregulated epigenetic states also create selective and targetable liabilities. We performed domain-based CRISPR/Cas9 screens of human chromatin regulators and identified MPHOSPH8 (or MPP8), a component of the HUSH complex and repressor of LINE-1 retrotransposons, as a selective epigenetic dependency of AML cells. While dispensable for normal hematopoiesis, MPP8 loss inhibited AML initiation and maintenance by reactivating LINE-1 retrotransposons. Activation of endogenous or ectopic LINE-1 photocopied MPP8 loss, whereas blocking LINE-1 retrotransposition abrogated MPP8-deficiency-induced phenotypes. Reactivated LINE-1 retrotransposition increased DNA damage, activated cyclin-dependent kinase inhibitor p21 (or CDKN1A), and induced AML differentiation. Enhanced L1 suppression in AML stem cells is associated with therapy resistance and poor prognosis. Hence, while retrotransposons are historically recognized as sources of genetic instability and somatic mutations, we uncover an unexpected role for HUSH/MPP8 in promoting cancer by suppressing genomic transposable elements.

2021-02-01 | GSE150982 | GEO

ChIP-seq analysis of H3K4me3, H3K9me3 and MPHOSPH8 in MOLM-13 cells

2021-02-01 | GSE150981 | GEO

The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s

Project description:The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s

| PRJNA559997 | ENA

MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells

Project description:Deciphering the mechanisms that control the pluripotent ground state is key for understanding embryonic development. Nonetheless, the epigenetic regulation of ground-state mouse embryonic stem cells (mESCs) is not fully understood. Here, we identify the epigenetic protein MPP8 as being essential for ground-state pluripotency. Its depletion leads to cell cycle arrest and spontaneous differentiation. MPP8 has been suggested to repress LINE1 elements by recruiting the human silencing hub (HUSH) complex to H3K9me3-rich regions. Unexpectedly, we find that LINE1 elements are efficiently repressed by MPP8 lacking the chromodomain, while the unannotated C-terminus is essential for its function. Moreover, we show that SETDB1 recruits MPP8 to its genomic target loci, whereas transcriptional repression of LINE1 elements is maintained without retaining H3K9me3 levels. Taken together our findings demonstrate that MPP8 protects the DNA-hypomethylated pluripotent ground state through its association with the HUSH core complex, however, independently of detectable chromatin binding and maintenance of H3K9me3.

2021-03-21 | PXD019345 | Pride

Mpp8 regulates the activity of LIF/STAT3 pathway in mouse embryonic stem cells

Project description:Mouse embryonic stem cells (mESCs) possess remarkable characteristics of unlimited self-renewal and pluripotency, which render them highly valuable for both fundamental research and clinical applications. A comprehensive understanding of the molecular mechanisms underlying mESC function is of utmost importance. The Human Silence Hub (HUSH) complex, comprising FAM208A, MPP8, and periphilin, constitutes an epigenetic silencing complex involved in suppressing retroviruses and transposons during early embryonic development. However, its precise role in regulating mESC pluripotency and differentiation remains elusive. In this study, we generated homogenous miniIAA7 tagged Mpp8 mouse ES cell lines. Upon induction of MPP8 protein degradation, we observed impaired proliferation and reduced colony formation ability of mESCs. Furthermore, this study unveils the involvement of MPP8 in regulating the activity of the LIF/STAT3 signaling pathway and Nanog expression in mESCs. Finally, we provide compelling evidence that degradation of the MPP8 protein impairs the differentiation of mESC.

2023-12-31 | E-MTAB-13214 | biostudies-arrayexpress

MPP8 is essential for sustaining self-renewal of ground-state pluripotent stem cells

Project description:Deciphering the mechanisms that control the pluripotent ground state is key for understanding embryonic development. Nonetheless, the epigenetic regulation of ground-state mouse embryonic stem cells (mESCs) is not fully understood. Here, we identify the epigentic protein MPP8 as being essential for ground-state pluripotency. Its depletion leads to cell cycle arrest and spontaneous differentiation. MPP8 has been suggested to repress LINE1 elements by recruiting the human silencing hub (HUSH) complex to H3K9me3-rich regions. Unexpectedly, we find that LINE1 elements are efficiently repressed by MPP8 lacking the chromodomain, while the unannotated C-terminus is essential for its function. Moreover, we show that SETDB1 recruits MPP8 to its genomic target loci, whereas transcriptional repression of LINE1 elements is maintained without retaining H3K9me3 levels. Taken together our findings demonstrate that MPP8 protects the DNA-hypomethylated pluripotent ground state through its association with the HUSH core complex, however, independently of detectable chromatin binding and maintenance of H3K9me3.

2021-03-14 | GSE150926 | GEO

DNA methylation status determines the sensitivity of repeats to restriction by the HUSH-MORC2 complex

Project description:The human silencing hub (HUSH) complex binds to transcripts of LINE-1 retrotransposons (L1s) and other genomic repeats, recruiting MORC2 and other effectors to remodel chromatin. However, how HUSH and MORC2 operate alongside DNA methylation, a central epigenetic regulator of repeat transcription, remains poorly understood. Here we interrogate this relationship in human neural progenitor cells (hNPCs), a somatic model of brain development that tolerates removal of DNA methyltransferase DNMT1. Upon loss of MORC2 or HUSH subunit TASOR in hNPCs, L1s remain silenced by robust promoter methylation. However, genome demethylation and activation of evolutionarily-young L1s attracts MORC2 binding. Simultaneous depletion of DNMT1 and MORC2 causes massive accumulation of L1 transcripts. We identify the same mechanistic hierarchy at pericentromeric α-satellites and clustered protocadherin genes, repetitive elements important for chromosome structure and neurodevelopment respectively. Our data delineate the independent epigenetic control of repeats in somatic cells, with implications for understanding the vital functions of HUSH-MORC2 in hypomethylated contexts throughout human development.

2024-03-26 | GSE242143 | GEO

Genome surveillance through repression of intronless mobile elements by the HUSH complex

Project description:All life forms defend their genome against DNA invasion. Eukaryotic cells recognize incoming DNA and limit transcription through repressive chromatin modifications. The human silencing hub (HUSH) complex transcriptionally represses long interspersed element-1 retrotransposons (L1s) and retroviruses through histone H3 Lys9 trimethylation (H3K9me3). How HUSH recognizes and initiates silencing of these invading genetic elements is unknown. Here, we show that HUSH is able to recognize and transcriptionally repress a broad range of long, intronless transgenes. Intron insertion into HUSH-repressed transgenes counteracts repression, even in the absence of intron splicing. HUSH binds transcripts from the target locus, prior to and independent of H3K9me3 deposition, and target transcription is essential for both initiation and propagation of HUSH-mediated H3K9me3. Genomic data reveals how HUSH binds and represses a subset of endogenous intronless genes generated through retrotransposition of cellular mRNAs. Therefore, intronless cDNA, a hallmark of reverse transcription, provides a versatile means to distinguish invading retroelements from host genes and allows HUSH to protect the genome from ‘non-self’ DNA, despite no prior exposure to the invading element. Our findings reveal the existence of a genome surveillance system and explain how it provides immediate protection against newly acquired elements while avoiding inappropriate repression of host genes.

2021-09-30 | GSE181113 | GEO

Co-transcriptional genome surveillance by HUSH is coupled to termination (CLIP-Seq)

Project description:The HUSH complex recognizes and silences foreign DNA such as viruses, transposons, and transgenes without prior exposure to its targets. Recent studies revealed that HUSH recruitment is dependent on transcription, but a unifying molecular mechanism by which HUSH identifies its targets as ‘non-self’ DNA and selects them for silencing remains unknown. Harnessing a de novo silencing event in ESCs, we uncover distinct modes of HUSH function – one involves co-transcriptional surveillance in the absence of silencing, while the other is associated with H3K9me3 deposition and repression. We demonstrate that HUSH travels with elongating RNAPII, interacts with the transcriptional termination machinery, and accumulates on chromatin in a manner dependent on the termination factor WDR82. We further show that perturbation of endogenous termination signals triggers the switch from HUSH surveillance to silencing. Together, our results uncover an RNAi-independent, co-transcriptional gene silencing mechanism in mammals that senses aberrant termination to distinguish self from non-self.

2023-05-09 | GSE208751 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data