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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE150981 | GEO | 2021/02/01

REPOSITORIES: GEO

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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

Transcriptional changes upon Mphosph8 loss in mouse brains on postnatal day 14.

Project description:We report that murine MPP8 and MORC2A are highly expressed in the brain and exclusively found in neurons. We show that genetic inactivation of Mphosph8 (coding for MPP8) or Morc2a in the nervous system of mice leads to alterations in brain architecture, behavioral impairments and reduction of life span. By doing RNA-seq and ChIP-seq experiments, we found that MPP8 and MORC2A suppress the repetitive-like protocadherin gene cluster on mouse chromosome 18 in a H3K9me3-dependent manner.

2022-09-13 | GSE185328 | GEO

Transcriptional changes upon Mphosph8 or Morc2a loss in sorted neuronal nuclei of adult mouse brains.

2022-09-13 | GSE185329 | GEO

Genome-wide maps of H3K9me3 upon Mphosph8 or Morc2a loss in sorted neuronal nuclei of adult mouse brains.

2022-09-13 | GSE189755 | 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

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

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

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

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

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

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