Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181113 | GEO | 2021/09/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Asymmetric distribution of H3K9me3 at replicating DNA strands silences L1 retrotransposons during S phase

Project description:In higher eukaryotes, repetitive DNA sequences are transcriptionally silenced through histone H3 lysine 9 tri-methylation (H3K9me3). A loss of silencing of these elements leads to genome instability and human diseases, including cancer and aging1-3. While the role of H3K9me3 in the establishment and maintenance of heterochromatin and repression of DNA repeats has been extensively studied4-6, the pattern and mechanism underlying the partitioning of H3K9me3 at replicating DNA strands were unknown. Here, we report that H3K9me3 is preferentially transferred onto the leading strands of replication forks, which occurs predominantly at Long Interspersed Nuclear Element (LINE) retrotransposons that are theoretically transcribed at the head-on direction with replication fork movement. In contrast, all other modified forms of histones tested are distributed in a nearly symmetric manner at the leading and lagging strands. Mechanistically, the Human Silencing Hub (HUSH) complex interacts with the leading strand DNA polymerase Pol ε, and contributes to the asymmetric segregation of H3K9me3 during chromatin replication. Cells deficient for Pol ε (POLE3 and POLE4), the HUSH complex (MPP8 and TASOR), or cells expressing a MPP8 mutant defective of H3K9me3 binding, or TASOR mutants with reduced interaction with Pol ε, show compromised H3K9me3 asymmetry and increased LINE expression. These results reveal an unexpected mechanism whereby the HUSH complex functions with Pol ε to promote asymmetric H3K9me3 distribution at LINEs to suppress their expression during S phase.

2023-08-17 | GSE211192 | GEO

Co-transcriptional genome surveillance by HUSH is coupled to termination (PRO-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 | GSE208752 | GEO

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

2023-05-09 | GSE208751 | GEO

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

2023-05-09 | GSE208749 | GEO

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

2023-05-09 | GSE208748 | GEO

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

TASOR epigenetic repressor cooperates with a CNOT1 RNA degradation pathway to repress HIV

Project description:The Human Silencing Hub (HUSH) complex constituted of TASOR, MPP8 and Periphilin is involved in the spreading of H3K9me3 repressive marks across genes and transgenes such as ZNF encoding genes, ribosomal DNAs, retroelements, including LINE-1 elements, or the integrated HIV provirus. The deposit of these repressive marks leads to heterochromatin formation and inhibits gene expression. The precise mechanisms of HUSH-mediated silencing are still poorly understood, but HUSH presents structural homology with the RNA-induced transcriptional silencing (RITS) complex found in fission yeast. During transcription elongation by RNA polymerase II, RITS recruits a TRAMP-like RNA degradation complex composed of CNOT1 partners, MTR4 and the exosome, to ultimately repress gene expression via H3K9me3 deposit. Here, we show that TASOR depletion or HIV-2 Vpx expression, which induces TASOR degradation, increases the accumulation of transcripts derived from the HIV-1 LTR promoter at a post-transcriptional level. Furthermore, using a yeast 2-hybrid screen, we identified new TASOR partners involved in RNA metabolism including the RNA deadenylase CCR4-NOT complex scaffold CNOT1. TASOR and CNOT1 interact in vivo and synergistically repress HIV expression from its LTR. Similar to the RITS complex, we show that TASOR interacts and cooperates with MTR4 and the exosome. We also highlight an interaction between TASOR and RNA Polymerase II, predominantly under its elongating state, and between TASOR and some HUSH-targeted nascent transcripts. Finally, we show that TASOR overexpression facilitates the association of the aforementioned RNA degradation proteins with RNA polymerase II and is detected at transcriptional centers. Altogether, we propose that HUSH operates at the transcriptional and post-transcriptional levels to repress HIV proviral gene expression.

2021-11-11 | GSE184399 | GEO

Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators

Project description:Transposable elements (TEs) are now recognized not only as parasitic DNA, whose spread in the genome must be controlled by the host, but also as major players in shaping genome evolution and providing genetic substrates for evolving new regulatory functions. Long INterspersed Element-1 (LINE-1 or L1), the only currently autonomous mobile transposon in humans, occupies 17% of the genome and continues to generate inter- and intra-individual genetic variation, in some cases resulting in disease. Nonetheless, our knowledge of how L1 activity is controlled and what function L1s play in host gene regulation remains fragmentary. Here, we use CRISPR/Cas9 screening strategies in two distinct human cell lines to provide the first genome-wide survey of genes involved in L1 retrotransposition control. Through this approach we identified functionally diverse genes that either promote or restrict L1 retrotransposition. These factors control the L1 life cycle at transcriptional or post-transcriptional levels, and in a manner which in some, but not in other cases depends on the endogenous L1 sequence, underscoring the complexity of L1 regulation. We further investigated L1 restriction by three candidate regulators, MORC2 and HUSH (human silencing hub) complex subunits TASOR and MPP8. HUSH/MORC2 selectively bind evolutionarily young, full-length L1s immersed within transcriptionally permissive euchromatic environment, and promote H3K9me3 deposition for transcriptional silencing. Interestingly, these silencing events often occur within introns of transcriptionally active host genes, and lead to down-regulation of host gene expression in a HUSH/MORC2-dependent manner. Together, our data provide a rich resource for studies of L1 retrotransposition, elucidate a novel L1 restriction pathway, and illustrate how epigenetic silencing of TEs can influence host gene expression programs.

2017-12-06 | GSE95374 | GEO

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

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

| PRJNA750731 | ENA

Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 lysine 36

Project description:Several lines of recent evidence support a role for chromatin in splicing regulation. Here we show that splicing can also contribute to histone modification, which implies a bidirectional communication between epigenetics and RNA processing. Genome-wide analysis of histone methylation in human cell lines and mouse primary T cells reveals that intron-containing genes are preferentially marked with H3K36me3 relative to intronless genes. In intron-containing genes, H3K36me3 marking is proportional to transcriptional activity, whereas in intronless genes H3K36me3 is always detected at much lower levels. Furthermore, splicing inhibition impairs recruitment of H3K36 methyltransferase HYPB/Setd2 and reduces H3K36me3, whereas splicing activation has the opposite effect. Moreover, the increase of H3K36me3 correlates with the length of the first intron, consistent with the view that splicing enhances H3 methylation. We propose that splicing is mechanistically coupled to recruitment of HYPB/Setd2 to elongating RNA Polymerase II.

2011-07-25 | GSE30902 | 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