Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3

Nair, Vidya Padmanabhan; Liu, Hengyuan; Ciceri, Gabriele; Jungverdorben, Johannes; Frishman, Goar; Tchieu, Jason; Cederquist, Gustav Y.; Rothenaigner, Ina; Schorpp, Kenji; Klepper, Lena; Walsh, Ryan; Kim, Tae Wan; Cornacchia, Daniela; Ruepp, Andreas; Mayer, Jens; Hadian, Kamyar; Frishman, Dmitrij; Studer, Lorenz; Vincendeau, Michelle

doi:10.1016/j.stem.2021.05.003

Cited by 13 publications

(19 citation statements)

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“…RNA-seq showed that HML-2 overexpression upregulates neuronal development-related genes in cortical neurons. Interestingly, dopaminergic neurons generated from control or transgenic hESCs had no difference in morphology or MAP2 expression at day 50 [ 381 ]. Skariah et al confirmed the importance of Mov10 RNA helicase in brain development.…”

Section: The Role Of Tes In the Normal Function Of Neuronal Tissuementioning

confidence: 99%

The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology

Чеснокова

Beletskiy

Kolosov

2022

IJMS

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Transposable elements (TEs) have been extensively studied for decades. In recent years, the introduction of whole-genome and whole-transcriptome approaches, as well as single-cell resolution techniques, provided a breakthrough that uncovered TE involvement in host gene expression regulation underlying multiple normal and pathological processes. Of particular interest is increased TE activity in neuronal tissue, and specifically in the hippocampus, that was repeatedly demonstrated in multiple experiments. On the other hand, numerous neuropathologies are associated with TE dysregulation. Here, we provide a comprehensive review of literature about the role of TEs in neurons published over the last three decades. The first chapter of the present review describes known mechanisms of TE interaction with host genomes in general, with the focus on mammalian and human TEs; the second chapter provides examples of TE exaptation in normal neuronal tissue, including TE involvement in neuronal differentiation and plasticity; and the last chapter lists TE-related neuropathologies. We sought to provide specific molecular mechanisms of TE involvement in neuron-specific processes whenever possible; however, in many cases, only phenomenological reports were available. This underscores the importance of further studies in this area.

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Section: The Role Of Tes In the Normal Function Of Neuronal Tissuementioning

confidence: 99%

The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology

Чеснокова

Beletskiy

Kolosov

2022

IJMS

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“…Nair et al generated forebrain organoids and explored the effects of human endogenous retroviruses HERV-K(HML-2) using the H9-CRISPRa-HERVK(HML-2) system. They found that the high expression of HERV-K(HML-2) results in hyperactivation of neurodegeneration-related genes, thus exerting an important physiological effect on cortical layer formation in forebrain organoids [ 16 ]. A study focusing on retinal organoids using CRISPR/Cas9-derived RB1-null human embryonic stem cells (hESCs) revealed that the cell cycle regulator Retinoblastoma 1 (RB1) played an essential role in early human retina development.…”

Section: Discussionmentioning

confidence: 99%

“…The guided method needs extra growth factors to guide PSCs to specific committed lineages [ 90 ]. In the included paper, Matrigel has been mostly used as a scaffold to support neuroepithelial bud expansion and organoid formation [ 16 , 18 , 53 , 58 ]. For example, an elegant study has established PSCs-derived cerebral organoids and mapped human-specific expression in great ape forebrain development using single-nucleus RNA sequencing analysis, which illustrated dynamic divergence in the cortex and chromatin accessibility in the light of gene-regulatory network and genetic change [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…To date, a number of studies have reported that stem-cell-derived organoids using hydrogels could simulate many different types of tissues and organs, including the intestine [ 13 , 14 , 15 ], brain [ 16 , 17 , 18 ], retina [ 19 , 20 ], cardiac tissues [ 21 , 22 , 23 ], kidney [ 24 , 25 , 26 ], lung [ 27 , 28 ], various oral tissues with (tooth germ organoids [ 29 ], lingual epithelium organoids [ 30 ], salivary gland [ 31 ] and taste bud organoids [ 32 ]), liver [ 33 , 34 ], cartilage [ 35 ], and vascular tissues [ 17 ]. The most commonly used hydrogel is Matrigel, which plays a key role in 3D culture organoid technology due to it being enriched in various growth factors and extracellular matrix components (such as laminin, type 4 collagen, growth factors, etc.).…”

Section: Introductionmentioning

confidence: 99%

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Advances of Engineered Hydrogel Organoids within the Stem Cell Field: A Systematic Review

Yue

Liu

et al. 2022

Gels

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Organoids are novel in vitro cell culture models that enable stem cells (including pluripotent stem cells and adult stem cells) to grow and undergo self-organization within a three-dimensional microenvironment during the process of differentiation into target tissues. Such miniature structures not only recapitulate the histological and genetic characteristics of organs in vivo, but also form tissues with the capacity for self-renewal and further differentiation. Recent advances in biomaterial technology, particularly hydrogels, have provided opportunities to improve organoid cultures; by closely integrating the mechanical and chemical properties of the extracellular matrix microenvironment, with novel synthetic materials and stem cell biology. This systematic review critically examines recent advances in various strategies and techniques utilized for stem-cell-derived organoid culture, with particular emphasis on the application potential of hydrogel technology in organoid culture. We hope this will give a better understanding of organoid cultures for modelling diseases and tissue engineering applications.

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“…The NTRK fusion protein will be continuously active, triggering a permanent signal cascade that drives the spread and growth of NTRK fusion tumors, including lung cancer (Harada et al, 2021;Konig et al, 2021). Studies have shown that high HERV-K (HML-2) transcription alters cortical layer formation in forebrain organoids, and transcriptional activation leads to hyperactivation of NTRK3 expression and other neurodegeneration-related genes (Padmanabhan Nair et al, 2021). The top markedly enriched pathway for these HERV-K (HML-2) pol loci was glucuronidation, and recent studies have shown that glucuronidation increases in malignant tumors (Landmann et al, 2014;Zahreddine et al, 2014).…”

Section: (Continued)mentioning

confidence: 99%

Significant Upregulation of HERV-K (HML-2) Transcription Levels in Human Lung Cancer and Cancer Cells

Yang

Guo

et al. 2022

Front. Microbiol.

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Lung cancer is the second most common cancer worldwide and the leading cause of cancer death in the world. Therefore, there is an urgent need to develop new and effective biomarkers for diagnosis and treatment. Under this circumstance, human endogenous retroviruses (HERVs) were recently introduced as novel biomarkers for cancer diagnosis. This study focused on the correlation between lung cancer and HERV-K (HML-2) transcription levels. At the cellular level, different types of lung cancer cells and human normal lung epithelial cells were used to analyze the transcription levels of the HERV-K (HML-2) gag, pol, and env genes by RT–qPCR. At the level of lung cancer patients, blood samples with background information from 734 lung cancer patients and 96 healthy persons were collected to analyze the transcription levels of HERV-K (HML-2) gag, pol, and env genes. The results showed that the transcriptional levels of the HERV-K (HML-2) gag, pol, and env genes in lung cancer cells and lung cancer patient blood samples were significantly higher than those in the healthy controls, which was also verified by RNAScope ISH technology. In addition, we also found that there was a correlation between the abnormal transcription levels of HERV-K (HML-2) genes in lung cancer patients and the clinicopathological parameters of lung cancer. We also identified the distribution locations of the gag, pol, and env primer sequences on each chromosome and analyzed the function of these loci. In conclusion, HERV-K (HML-2) genes may be a potential biomarker for the diagnosis of lung cancer.

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Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3

Cited by 13 publications

References 0 publications

The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology

The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology

Advances of Engineered Hydrogel Organoids within the Stem Cell Field: A Systematic Review

Significant Upregulation of HERV-K (HML-2) Transcription Levels in Human Lung Cancer and Cancer Cells

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