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Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing

ABSTRACT: Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing

PROVIDER: PRJNA980677 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24837420_1.fastq.gz	Fastqsanger.gz
	SRR24837420_2.fastq.gz	Fastqsanger.gz
	SRR24837421_1.fastq.gz	Fastqsanger.gz
	SRR24837421_2.fastq.gz	Fastqsanger.gz
	SRR24837422_1.fastq.gz	Fastqsanger.gz

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Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing

Project description:The Human Silencing Hub (HuSH) complex is a complex that silences retrotransposable elements invertebrates. Here, we identify a second HuSH complex, designated HuSH2, which is centered aroundTASOR2, a paralog of the core TASOR protein in HuSH. Our findings reveal that HuSH and HuSH2 localize todistinct and non-overlapping genomic loci. Specifically, HuSH localizes to and represses LINE-1retrotransposons, whereas HuSH2 targets and represses KRAB-ZNFs and interferon signaling and responsegenes. We use in silico protein structure predictions to simulate MPP8 interactions with TASOR paralogs,guiding amino acid substitutions that disrupted binding to HuSH complexes. These MPP8 transgenes andother constructs reveal the importance of HuSH complex quantities in regulating LINE-1 activity. Furthermore,our results suggest that dynamic changes in TASOR and TASOR2 expression enable cells to finely tuneHuSH-mediated silencing. This study offers insights into the interplay of HuSH complexes, highlighting theirvital role in retrotransposon regulation.

2024-09-24 | PXD049085 | Pride

Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing [RNA-seq]

Project description:The Human Silencing Hub (HuSH) complex is a complex that silences retrotransposable elements in vertebrates. Here, we identify a second HuSH complex, designated HuSH2, which is centered around TASOR2, a paralog of the core TASOR protein in HuSH. Our findings reveal that HuSH and HuSH2 localize to distinct and non-overlapping genomic loci. Specifically, HuSH localizes to and represses LINE-1 retrotransposons, whereas HuSH2 targets and represses KRAB-ZNFs and interferon signaling and response genes. We use in silico protein structure predictions to simulate MPP8 interactions with TASOR paralogs, guiding amino acid substitutions that disrupted binding to HuSH complexes. These MPP8 transgenes and other constructs reveal the importance of HuSH complex quantities in regulating LINE-1 activity. Furthermore, our results suggest that dynamic changes in TASOR and TASOR2 expression enable cells to finely tune HuSH-mediated silencing. This study offers insights into the interplay of HuSH complexes, highlighting their vital role in retrotransposon regulation.

2024-09-23 | GSE234280 | GEO

Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing [ChIP-seq]

Project description:The Human Silencing Hub (HuSH) complex is a complex that silences retrotransposable elements in vertebrates. Here, we identify a second HuSH complex, designated HuSH2, which is centered around TASOR2, a paralog of the core TASOR protein in HuSH. Our findings reveal that HuSH and HuSH2 localize to distinct and non-overlapping genomic loci. Specifically, HuSH localizes to and represses LINE-1 retrotransposons, whereas HuSH2 targets and represses KRAB-ZNFs and interferon signaling and response genes. We use in silico protein structure predictions to simulate MPP8 interactions with TASOR paralogs, guiding amino acid substitutions that disrupted binding to HuSH complexes. These MPP8 transgenes and other constructs reveal the importance of HuSH complex quantities in regulating LINE-1 activity. Furthermore, our results suggest that dynamic changes in TASOR and TASOR2 expression enable cells to finely tune HuSH-mediated silencing. This study offers insights into the interplay of HuSH complexes, highlighting their vital role in retrotransposon regulation.

2024-09-23 | GSE234279 | GEO

Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing [RNA-seq]

Project description:Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing [RNA-seq]

| PRJNA980681 | ENA

Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing [ChIP-seq]

Project description:Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing [ChIP-seq]

| PRJNA980682 | ENA

Interplay between Two Paralogous Human Silencing Hub (HuSH) Complexes in Regulating LINE-1 Element Silencing

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-09-23 | GSE234281 | GEO

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 binding by Periphilin plays an essential role in initiating silencing by the HUSH complex

Project description:The human silencing hub (HUSH) complex is a transcription-dependent, epigenetic repressor complex that provides a genome-wide immunosurveillance system for the recognition and silencing of newly-integrated retroelements. The core HUSH complex of TASOR, MPP8 and Periphilin, represses these retroelements through SETDB1-mediated H3K9me3 deposition and MORC2-dependent chromatin compaction. HUSH-dependent silencing is RNA-mediated, yet no HUSH components encode any RNA-binding domain. Here we used an unbiased approach to identify which HUSH component was able to bind RNA and determine whether RNA-binding was essential for HUSH function. We identify Periphilin as the major RNA-binding component of the HUSH complex and show that Periphilin’s N-terminal domain is essential for both RNA binding and HUSH function. Periphilin binding to RNA was independent of its interaction with TASOR or MPP8, as its N-terminal domain was sufficient for RNA targeting. The artificial tethering of Periphilin, to a HUSH-insensitive, nascent transcript, enabled the HUSH-dependent silencing of the transcript. This tethering of Periphilin allowed the RNA-binding region of Periphilin to be removed such that only its C-terminal domain was required, for oligomerisation and interaction with TASOR. We therefore show that Periphilin is the predominant RNA-binding protein of the HUSH complex and this RNA-binding is essential for HUSH activity.

2024-11-11 | GSE272315 | 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

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

Project description: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.

2020-09-28 | GSE135765 | GEO

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