Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE211192 | GEO | 2023/08/17

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

Assessing the impact of loss of IRF2 on TASOR2 localization

Project description:The HUSH complex preserves genome integrity through the epigenetic repression of invasive genetic elements. However, despite our understanding of HUSH as an obligate complex of three subunits, only loss of MPP8 or Periphilin, but not TASOR, triggers interferon signaling following derepression of endogenous retroelements. Here we resolve this paradox by characterising a second HUSH complex which shares MPP8 and Periphilin but assembles around TASOR2, an uncharacterized paralog of TASOR. Whereas HUSH represses LINE-1 retroelements marked by the repressive histone modification H3K9me3, HUSH2 is recruited by the transcription factor IRF2 to repress interferon-stimulated genes. Mechanistically, HUSH-mediated retroelement silencing sequesters the limited pool of the shared subunits MPP8 and Periphilin, preventing TASOR2 from forming HUSH2 complexes and hence relieving the HUSH2-mediated repression of interferon-stimulated genes. Thus, competition between two HUSH complexes intertwines retroelement silencing with the induction of an immune response, coupling epigenetic and immune aspects of genome defense.

2024-07-15 | GSE269262 | GEO

Assessing the impact of loss of IRF2 on the transcriptome

2024-07-15 | GSE268798 | GEO

Assessing the impact of loss of HUSH or HUSH2 subunits on the transcriptome

2024-07-15 | GSE268797 | GEO

Profiling the genome-wide distribution of TASOR2 upon expression of a LINE-1 reporter or Vpx

2024-07-15 | GSE268796 | GEO

Profiling the genome-wide distribution of HUSH2 subunits

2024-07-15 | GSE268795 | GEO

Profiling the genome-wide distribution of HUSH subunits

2024-07-15 | GSE268794 | 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

Asymmetric partition of parental histone (H3-H4)2 tetramers onto replicating DNA strands

Project description:In eukaryotic cells, inheritable changes in gene expression in response to environmental and developmental stimuli is associated with changes in histone modifications and relies on the passage of these changes into daughter cells during cell division, a process that remains elusive. Here, we show that parental histone (H3-H4)2 tetramers, the primary carrier of epigenetic modifications, are assembled into nucleosomes onto both replicating leading and lagging strands, with a preference for lagging strands of DNA replication forks. This asymmetric distribution of parental (H3-H4)2 is exacerbated in cells lacking Dpb3 and Dpb4, two subunits of DNA polymerase Pol ε. Dpb3-Dpb4 binds (H3-H4)2 and participates in the transfer of parental (H3-H4)2 tetramers onto leading strands of DNA replication forks. Cells lacking Dpb3 and Dpb4 exhibits defects in epigenetic inheritance. These results reveal a previously undocumented mechanism of histone segregation and a direct role for Pol ε in this poorly understood process.

2018-08-28 | GSE112522 | 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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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