Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia

Gu, Zhimin; Liu, Yuxuan; Zhang, Yuannyu; Cao, Hui; Lyu, Junhua; Wang, Xun; Wylie, Annika; Newkirk, Simon J.; Jones, Amanda E.; Lee, Michael; Botten, Giovanni A.; Deng, Mi; Dickerson, Kathryn E.; Zhang, Cheng Cheng; An, Wenfeng; Abrams, John; Xu, Jian

doi:10.1038/s41588-021-00829-8

Cited by 61 publications

(66 citation statements)

References 81 publications

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“…1g,h). In comparison to a recent study showing that Mphosph8 knock-out mice display partial embryonic lethality with surviving Mphosph8 -/- mice developing normally apart from reduced body weight 14 , in our study Actin -Cre-mediated loss of Mphosph8 resulted in 100% embryonic lethality before embryonic day 11.5 (E11.5) and loss of Morc2a led to embryonic lethality around E13.5 (Extended Data Fig. 1i,j).…”

Section: Resultscontrasting

confidence: 61%

The HUSH complex controls brain architecture and protocadherin fidelity

Hagelkrüys

Horrer

Taubenschmid-Stowers

et al. 2021

Preprint

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Fine-tuning of neural connectivity is important for cerebral functions and brain evolution. Protocadherins provide barcodes for neuronal identity as well as synapse formation and expansion of protocadherin cluster genes has been linked to advanced cognitive functions. The tightly controlled stochastic and combinatorial expression of the different protocadherin isoforms in individual neurons provides the molecular basis for neuronal diversity, neuronal network complexity and function of the vertebrate brain. How protocadherins are epigenetically controlled has not yet been fully elucidated. Here we show that the HUSH (human silencing hub) complex containing H3K9me3 binding protein M-phase phosphoprotein 8 (MPP8) and Microrchidia CW-type zinc finger protein 2 (MORC2), critically controls the fidelity of protocadherin expression. MPP8 and MORC2A are highly expressed in the murine brain and exclusively found in neurons. Genetic inactivation of Mphosph8 (coding for MPP8) or Morc2a in the nervous system of mice leads to increased brain size, altered brain architecture, and behavioral changes. Mechanistically, MPP8 and MORC2A precisely and selectively suppress the repetitive-like protocadherin gene cluster on mouse chromosome 18 in a H3K9me3-dependent manner, thereby affecting synapse formation. Moreover, we demonstrate that individual MPHOSPH8- or MORC2-deficient neurons in human cerebral organoids express increased numbers of clustered protocadherin isoforms. Our data identify the HUSH complex, previously linked to silencing of repetitive transposable elements, as a key epigenetic regulator of protocadherin expression in the nervous system and thereby brain development and neuronal individuality in mice and humans.

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Section: Resultscontrasting

confidence: 61%

The HUSH complex controls brain architecture and protocadherin fidelity

Hagelkrüys

Horrer

Taubenschmid-Stowers

et al. 2021

Preprint

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“…However, by their capacity to induce DNA damage and activate cell cycle arrest, senescence and inflammatory responses, these sequences may also be viewed as tumor suppressors (Grundy et al, 2021; Kelsey, 2021). TE expression, and notably that of active full-length L1 capable of retrotranspositoin (L1Hs) is decreased in AML and MDS samples as compared to healthy CD34 + progenitor cells (Kazachenka et al, 2019; Gu et al, 2021). In AML, oncogenic mutations leading to L1 epigenetic silencing are selected and associate with poorer prognosis (Gu et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…TE expression, and notably that of active full-length L1 capable of retrotranspositoin (L1Hs) is decreased in AML and MDS samples as compared to healthy CD34 + progenitor cells (Kazachenka et al, 2019; Gu et al, 2021). In AML, oncogenic mutations leading to L1 epigenetic silencing are selected and associate with poorer prognosis (Gu et al, 2021). Likewise, increased expression of the H3K9me3 methyltransferase SETDB1 is responsible for TE silencing in AML cell lines and is required for their survival (Cuellar et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

The NF-κB pathway controls H3K9me3 levels at intronic LINE-1 elements and hematopoietic stem cell gene expression in cis

Pelinski

Hidaoui

Hermetet

et al. 2021

Preprint

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Understanding how ionizing radiations (IR) alter hematopoietic stem cell (HSC) function on the long-term is crucial. We recently showed a link between derepression of L1Md, the mouse young subfamilies of LINE-1/L1 retroelements, and IR-induced HSC injury. L1 contribute to gene regulatory networks. However, the mechanisms involved in IR-induced L1Md derepression, and their impact on HSC transcriptome remain to be addressed. Here we show that IR triggers genome-wide H3K9me3 decreased and transcriptomic changes in HSCs, characterized by a loss of the TNF-α/NF-κB and HSC signatures. HSC gene repression is associated to H3K9me3 loss at specific intronic L1Md displaying NF-κB binding sites. This is correlated with reduced NFKB1 repressor expression. TNF-α treatment before IR rescued all these effects and prevented IR-induced HSC loss of function in vivo. This reveals the importance of the TNF-α/NF-κB pathway to control H3K9me3 levels at selected intronic L1Md and thereby preserve HSC gene expression and function during IR stress.

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“…In these cases, demethylating agents increased transcription of TEs that were sensed by MDA5 thus leading to induction of inflammatory responses and subsequently to cell death [83][84][85]. Similarly, upregulation of LINE1 upon loss of MPHOSPH8 or MPP8 (M-Phase Phosphoprotein), a member of the HUSH complex, resulted in DNA damage and tumor regression or arrest [86]. The implication from these studies is that triggering RNA-sensing pathways could be instrumental for some cancer immunotherapeutic approaches.…”

Section: Rig-ing Stemnessmentioning

confidence: 97%

Sensing Stemness

Bowman

Trompouki

2021

Curr Stem Cell Rep

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Purpose of Review Hematopoietic stem cells (HSCs) are formed embryonically during a dynamic developmental process and later reside in adult hematopoietic organs in a quiescent state. In response to their changing environment, HSCs have evolved diverse mechanisms to cope with intrinsic and extrinsic challenges. This review intends to discuss how HSCs and other stem cells co-opted DNA and RNA innate immune pathways to fine-tune developmental processes. Recent Findings Innate immune receptors for nucleic acids like the RIG-I-like family receptors and members of DNA sensing pathways are expressed in HSCs and other stem cells. Even though the “classic” role of these receptors is recognition of foreign DNA or RNA from pathogens, it was recently shown that cellular transposable element (TE) RNA or R-loops activate such receptors, serving as endogenous triggers of inflammatory signaling that can shape HSC formation during development and regeneration. Summary Endogenous TEs and R-loops activate RNA and DNA sensors, which trigger distinct inflammatory signals to fine-tune stem cell decisions. This phenomenon could have broad implications for diverse somatic stem cells, for a variety of diseases and during aging.

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Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia

Cited by 61 publications

References 81 publications

The HUSH complex controls brain architecture and protocadherin fidelity

The HUSH complex controls brain architecture and protocadherin fidelity

The NF-κB pathway controls H3K9me3 levels at intronic LINE-1 elements and hematopoietic stem cell gene expression in cis

Sensing Stemness

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