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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE150926 | GEO | 2021/03/14

REPOSITORIES: GEO

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

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

| PRJNA634099 | ENA

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

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

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

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

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

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

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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