­­­Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia­­

Cuellar, Trinna; Herzner, Anna‐Maria; Zhang, Xiaotian; Goyal, Yogesh; Watanabe, Colin; Friedman, Brad A.; Janakiraman, Vasantharajan; Durinck, Steffen; Stinson, Jeremy; Arnott, David; Cheung, Tommy K.; Chaudhuri, Subhra; Modrušan, Zora; Doerr, Jonas; Classon, Marie; Haley, Benjamin

doi:10.1083/jcb.201612160

Cited by 148 publications

(167 citation statements)

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“…Future work will be necessary to determine exactly which factors act in addition to KAP1 to maintain ERV silencing in differentiated cells. Many epigenetic regulators exert cross‐talk with DNA methylation including SETDB1 , which can act independently or in concert with KAP1 and which itself has a reported role in innate immune control in cancer cells . Another key question concerns the identities of the potential immuno‐stimulatory RNAs that may derive from retrotransposons producing secondary structure.…”

Section: Discussionmentioning

confidence: 99%

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KAP 1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control

Tie

Fernandes

Conde³

et al. 2018

EMBO Reports

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Endogenous retroviruses (ERVs) have accumulated in vertebrate genomes and contribute to the complexity of gene regulation. KAP1 represses ERVs during development by its recruitment to their repetitive sequences through KRAB zinc‐finger proteins (KZNFs), but little is known about the regulation of ERVs in adult tissues. We observed that KAP1 repression of HERVK14C was conserved in differentiated human cells and performed KAP1 knockout to obtain an overview of KAP1 function. Our results show that KAP1 represses ERVs (including HERV‐T and HERV‐S) and ZNF genes, both of which overlap with KAP1 binding sites and H3K9me3 in multiple cell types. Furthermore, this pathway is functionally conserved in adult human peripheral blood mononuclear cells. Cytosine methylation that acts on KAP1 regulated loci is necessary to prevent an interferon response, and KAP1‐depletion leads to activation of some interferon‐stimulated genes. Finally, loss of KAP1 leads to a decrease in H3K9me3 enrichment at ERVs and ZNF genes and an RNA‐sensing response mediated through MAVS signaling. These data indicate that the KAP1‐KZNF pathway contributes to genome stability and innate immune control in adult human cells.

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Section: Discussionmentioning

confidence: 99%

“…DNA methylation including SETDB1 [47], which can act independently or in concert with KAP1 [25] and which itself has a reported role in innate immune control in cancer cells [23].…”

Section: Kap1 Regulates Ervs and Znf Genes In Differentiated Human Cementioning

confidence: 99%

KAP 1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control

Tie

Fernandes

Conde³

et al. 2018

EMBO Reports

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“…Furthermore, dsRNA detection can trigger interferon beta downstream of chromatin destabilization 53 .…”

Section: Discussionmentioning

confidence: 99%

“…These observations suggest that factors related to the accumulation of pathological Tau might trigger the interferon pathway through dsRNA detection. This is particularly salient based upon the recent observation that pathological Tau drives chromatin destabilization 73,74 , a known source of endogenous dsRNA that can activate Ifih1 (MDA5) and trigger an interferon response 44,53 . Combined, our results present a parsimonious model wherein dsRNA, released following chromatin destabilization in injured neurons in response to Tau pathology, may active chronic immune activation pathways to suppress specific immune signaling (the inflammasome module) and activate anti-inflammasome pathways to alter cellular functions including protein ubiquitination, autophagy, exosome formation, and translation 75 (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Dementia risk genes engage gene networks poised to tune the immune response towards chronic inflammatory states

Rexach

Swarup

Chang

et al. 2019

Preprint

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An emerging challenge in neurodegenerative dementia is understanding how immune-associated genes and pathways contribute to disease. To achieve a refined view of neuroinflammatory signaling across neurodegeneration, we took an integrative functional genomics approach to consider neurodegeneration from the perspective of microglia and their interactions with other cells. Using large-scale gene expression and perturbation data, regulatory motif analysis, and gene knockout studies, we identify and characterize a microglial-centric network involving distinct gene co-expression modules associated with progressive stages of neurodegeneration. These modules, which are conserved from mouse to human, differentially incorporate specific immune sensors of cellular damage and pathways that are predicted to eventually tune the immune response toward chronic inflammation and immune suppression. Notably, common genetic risk for Alzheimer's disease (AD), Frontotemporal dementia (FTD) and Progressive Supranuclear Palsy (PSP) resides in specific modules that distinguish between the disorders, but also show convergence on pathways related to anti-viral defense mechanisms. These results suggest a model wherein combinatorial microglial-immune signaling integrate specific immune activators and disease genes that lead to the establishment of chronic states of simultaneous inflammation and immunosuppression involving type 1 interferon in these dementias.

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Improving Cancer Immunotherapy with CRISPR‐Based Technology

Teng

2020

Adv. Biosys.

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cancer immunology. Adoptive cell transfer (ACT) with tumor-infiltrating lymphocytes (TILs) was tested to treat melanoma cancer patients in 1980s. [5] Monoclonal antibodies (mAbs) targeting tumor-specific or highly expressed surface antigens were approved by the U.S. Food and Drug Administration (FDA) for cancer treatment in late 1990s, for example, mAb Rituximab targeting B cell marker CD20 was approved in 1997 for non-Hodgkin's lymphoma and mAb Trastuzumab (Herceptin) targeting highly expressed human epidermal growth factor like receptor 2 (HER2) was approved in 1998 for HER2-positive breast cancer. Cytokines like interleukin-2 (IL-2) that can augment the anti-tumor immune response were also approved in 1998 to treat metastatic melanoma patients. The first FDAapproved cancer vaccine was developed in 2010 under the brand name of 'Provenge' (sipuleucel-T) that works as an autologous dendritic cell-based vaccine for the treatment of advanced prostate cancer. In the following year, the first immune checkpoint inhibitor anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) antibody was approved as a novel licensed drug for treating metastatic melanoma. Therapies with genetically engineered T cells expressing chimeric antigen receptor (CAR-T cell therapy) also stepped onto stage as approved cancer drugs in 2017 with the first one "Kymriah" targeting a B cell antigen CD19 for the treatment of refractory pre-B cell acute lymphoblastic leukemia and diffuse large B cell lymphoma. In addition, there are many ongoing immunotherapy clinical trials that have been showing impressive anti-tumor response and clinical benefits. With these explosive progresses in this field, Science magazine named cancer immunotherapy as "Breakthrough of the Year" in 2013. [6] Furthermore, the 2018 Nobel Prize in physiology and medicine was awarded to Dr. Allison and Dr. Honjo for their contributions to immune checkpoint cancer therapy. Genome editing technology is a fundamental platform for modern biomedical research, which enables people to precisely manipulate the genetic materials in cells or organisms. This technique can be either applied as research tools or ways of therapeutic intervention for gene therapy or engineered cell therapy. Several engineered nucleases such as zinc-finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and meganuclease have been designed to fulfill the DNA scissors function for genome editing, however, the editing efficiency, ease of use, timing and cost issues collectively limit

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Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia

Cited by 148 publications

References 78 publications

KAP 1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control

KAP 1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control

Dementia risk genes engage gene networks poised to tune the immune response towards chronic inflammatory states

Improving Cancer Immunotherapy with CRISPR‐Based Technology

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­­­Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia­­

Cited by 148 publications

References 78 publications

KAP 1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control

KAP 1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control

Dementia risk genes engage gene networks poised to tune the immune response towards chronic inflammatory states

Improving Cancer Immunotherapy with CRISPR‐Based Technology

Contact Info

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Resources

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Silencing of retrotransposons by SETDB1 inhibits the interferon response in acute myeloid leukemia