Periodic Reporting for period 5 - TransposonsReprogram (How retrotransposons remodel the genome during early development and reprogramming)
Reporting period: 2023-01-01 to 2023-09-30
How retrotransposons remodel the genome during early development and reprogramming
The overall goal, objectives and why this research is important for society
Genes are the basic building blocks that give our cells instructions to make proteins and carry out day-to-day functions, such as generating energy and protecting us from disease. Surprisingly only around 2% of our DNA codes for genes. Most of the rest of our DNA has an unknown function and is referred to as genomic dark matter. Understanding this dark part of the genome will allow us to make new discoveries about how diseases arise and will enable us to harness this part of the genome in new medicines. A closer look at the dark genome reveals that most of it is comprised of ancient virus-like elements, most of which have used a copy-and-paste mechanism to make new copies of their own DNA to insert into our genome, allowing for their stable inheritance. These viruses are called transposable elements (TEs) and while they once replicated, the majority of these elements are now dormant or extinct, due to their mutation. The overall goal of our ERC starting grant was to understand how these TEs (DNA sequences of viral-like origin) have been beneficially repurposed in mammals to allow normal progression through development. This knowledge is relevant to the development of stem cell therapies and to understanding and combating cancer where cells can reprogram to adopt a stem cell-like fate, which is central to cancer remissions and metastases. More broadly, this research has allowed us to understand how mutations within genomic non-coding regions, including microsatellite instability can lead to diseases, such as cancer or Aicardi Goutières Syndrome. We hypothesized that ancient transposon-derived DNA sequences would function in cell fate transitions in early development and during reprogramming and have discovered this to indeed be the case.
Summary image caption (see the summary image)
Conclusions
We discovered a new mechanism of gene regulation that regulates developmental fate transitions. Specifically, we identified a part of ‘genomic dark matter’ in the form of an array of satellite repeat DNAs that form a ‘barcode’ across mouse chromosome 7. This array embeds a cluster of genes encoding a master transcription factor regulator of totipotency, known as ZSCAN4. We show that the KRAB-zinc finger protein, ZFP819 binds to this satellite array to initiate the formation of heterochromatin across it, which silences expression of the totipotency gene expression program, allowing mouse embryos to exit from totipotency and progress through development. This work is relevant to understanding development, to stem cell therapies and to treating cancer because cancer cells manipulate the same gene regulatory mechanisms in order to adopt a cancer stem cell-like fate. We also found that another zinc finger protein, ZFP37 regulates neural cell fate through binding to active endogenous retroviruses, corroborating our original hypothesis that genomic dark matter has been co-opted by mammalian genomes to regulate cell fate and reprogramming. Transposable elements often jump into genes expressed in the brain illustrating that our research is relevant to understanding neurodevelopmental diseases. Finally we identify which transposable elements are subject to epigenetic silencing and why: We show that epigenetic silencing is concentrated towards the most pathogenic transposable elements in the genome, which are the ones still capable of replicating within the genome or ‘jumping’. We find that when epigenetic silencing is impaired, uncontrolled expression of transposable elements leads to a type 1 interferon response. On the other hand, transposable elements that undergo mutations, which cause them to lose the ability to jump also lose vital sequences necessary for recruiting epigenetic repressors. This allows them to evolve beneficial roles in gene regulation. This also sheds light on why cancers exhibiting epigenetic dysregulation undergo a derepression of transposable elements that are capable of jumping. Our work published in Science Advances, Nature Communications and Cell Reports illustrates how the host-pathogen evolutionary arms race is closely intertwined with the evolution of host gene regulatory networks.
Main Citation links:
https://www.science.org/doi/epdf/10.1126/sciadv.abp8085
https://www.nature.com/articles/s41467-020-19170-5
https://www.cell.com/action/showPdf?pii=S2211-1247%2823%2900636-8
The overall goal, objectives and why this research is important for society
Genes are the basic building blocks that give our cells instructions to make proteins and carry out day-to-day functions, such as generating energy and protecting us from disease. Surprisingly only around 2% of our DNA codes for genes. Most of the rest of our DNA has an unknown function and is referred to as genomic dark matter. Understanding this dark part of the genome will allow us to make new discoveries about how diseases arise and will enable us to harness this part of the genome in new medicines. A closer look at the dark genome reveals that most of it is comprised of ancient virus-like elements, most of which have used a copy-and-paste mechanism to make new copies of their own DNA to insert into our genome, allowing for their stable inheritance. These viruses are called transposable elements (TEs) and while they once replicated, the majority of these elements are now dormant or extinct, due to their mutation. The overall goal of our ERC starting grant was to understand how these TEs (DNA sequences of viral-like origin) have been beneficially repurposed in mammals to allow normal progression through development. This knowledge is relevant to the development of stem cell therapies and to understanding and combating cancer where cells can reprogram to adopt a stem cell-like fate, which is central to cancer remissions and metastases. More broadly, this research has allowed us to understand how mutations within genomic non-coding regions, including microsatellite instability can lead to diseases, such as cancer or Aicardi Goutières Syndrome. We hypothesized that ancient transposon-derived DNA sequences would function in cell fate transitions in early development and during reprogramming and have discovered this to indeed be the case.
Summary image caption (see the summary image)
Conclusions
We discovered a new mechanism of gene regulation that regulates developmental fate transitions. Specifically, we identified a part of ‘genomic dark matter’ in the form of an array of satellite repeat DNAs that form a ‘barcode’ across mouse chromosome 7. This array embeds a cluster of genes encoding a master transcription factor regulator of totipotency, known as ZSCAN4. We show that the KRAB-zinc finger protein, ZFP819 binds to this satellite array to initiate the formation of heterochromatin across it, which silences expression of the totipotency gene expression program, allowing mouse embryos to exit from totipotency and progress through development. This work is relevant to understanding development, to stem cell therapies and to treating cancer because cancer cells manipulate the same gene regulatory mechanisms in order to adopt a cancer stem cell-like fate. We also found that another zinc finger protein, ZFP37 regulates neural cell fate through binding to active endogenous retroviruses, corroborating our original hypothesis that genomic dark matter has been co-opted by mammalian genomes to regulate cell fate and reprogramming. Transposable elements often jump into genes expressed in the brain illustrating that our research is relevant to understanding neurodevelopmental diseases. Finally we identify which transposable elements are subject to epigenetic silencing and why: We show that epigenetic silencing is concentrated towards the most pathogenic transposable elements in the genome, which are the ones still capable of replicating within the genome or ‘jumping’. We find that when epigenetic silencing is impaired, uncontrolled expression of transposable elements leads to a type 1 interferon response. On the other hand, transposable elements that undergo mutations, which cause them to lose the ability to jump also lose vital sequences necessary for recruiting epigenetic repressors. This allows them to evolve beneficial roles in gene regulation. This also sheds light on why cancers exhibiting epigenetic dysregulation undergo a derepression of transposable elements that are capable of jumping. Our work published in Science Advances, Nature Communications and Cell Reports illustrates how the host-pathogen evolutionary arms race is closely intertwined with the evolution of host gene regulatory networks.
Main Citation links:
https://www.science.org/doi/epdf/10.1126/sciadv.abp8085
https://www.nature.com/articles/s41467-020-19170-5
https://www.cell.com/action/showPdf?pii=S2211-1247%2823%2900636-8
Most of the main results from our ERC funded work are now published in the following three peer reviewed research articles:
1.Fernandes L.P. Enriquez-Gasca, R., Gould, P.A. Holt, J.H. Conde, L., Ecco, G., Herrero, J., Gifford, R., Trono, D., Kassiotis, G., Rowe, H.M. 2022. A satellite DNA array barcodes chromosome 7 and regulates totipotency via ZFP819. Sci Adv 8, eabp8085.
Here, we identify a new mechanism of gene regulation likely to be widely applicable.
Highlighted by ESC and iPSC news, a news service for the stem cell community
The above work involved development of molecular reagents that we have distributed to other labs and computational pipelines that we have developed in the form of digital workshops in the below international course:
https://www.insb.cnrs.fr/fr/qlife-winter-school-genomics-transposable-elements-unmasking-their-complex-contribution-genome
2.Tunbak H.*, Enriquez-Gasca, R.*, Tie, C.H.C. Gould, P.A. Mlcochova, P., Gupta, R.K. Fernandes, L., Holt, J., van der Veen, A.G. Giampazolias, E., Burns, K.H. Maillard, P.V. Rowe, H.M. 2020. The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s. Nature communications 11, 5387.
Here, we identify a chromatin regulator that acts as an Achilles heel of the immune system because its inactivation leads to a type 1 interferon response reminiscent of sterile inflammation.
The above work was highlighted in the Editors’ highlights in Nature Communications and involved the generation of molecular reagents that we have distributed to other labs and computational pipelines that we have developed in the form of digital workshops in the below international course:
https://www.insb.cnrs.fr/fr/qlife-winter-school-genomics-transposable-elements-unmasking-their-complex-contribution-genome
We have also disseminated original code:
https://github.com/regmdr/HUSH_analysis
3.Enriquez-Gasca R.*, Gould, P.A.* Tunbak, H., Conde, L., Herrero, J., Chittka, A., Beck, C.R. Gifford, R., Rowe, H.M. 2023. Co-option of endogenous retroviruses through genetic escape from TRIM28 repression. Cell Rep 42, 112625.
Here, we shed light on which endogenous retroviruses become repurposed by the host and why.
We disseminated this work as a preprint on bioRxiv before publishing it in Cell Reports and plan to disseminate our original molecular reagents and pipelines where requested.
1.Fernandes L.P. Enriquez-Gasca, R., Gould, P.A. Holt, J.H. Conde, L., Ecco, G., Herrero, J., Gifford, R., Trono, D., Kassiotis, G., Rowe, H.M. 2022. A satellite DNA array barcodes chromosome 7 and regulates totipotency via ZFP819. Sci Adv 8, eabp8085.
Here, we identify a new mechanism of gene regulation likely to be widely applicable.
Highlighted by ESC and iPSC news, a news service for the stem cell community
The above work involved development of molecular reagents that we have distributed to other labs and computational pipelines that we have developed in the form of digital workshops in the below international course:
https://www.insb.cnrs.fr/fr/qlife-winter-school-genomics-transposable-elements-unmasking-their-complex-contribution-genome
2.Tunbak H.*, Enriquez-Gasca, R.*, Tie, C.H.C. Gould, P.A. Mlcochova, P., Gupta, R.K. Fernandes, L., Holt, J., van der Veen, A.G. Giampazolias, E., Burns, K.H. Maillard, P.V. Rowe, H.M. 2020. The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s. Nature communications 11, 5387.
Here, we identify a chromatin regulator that acts as an Achilles heel of the immune system because its inactivation leads to a type 1 interferon response reminiscent of sterile inflammation.
The above work was highlighted in the Editors’ highlights in Nature Communications and involved the generation of molecular reagents that we have distributed to other labs and computational pipelines that we have developed in the form of digital workshops in the below international course:
https://www.insb.cnrs.fr/fr/qlife-winter-school-genomics-transposable-elements-unmasking-their-complex-contribution-genome
We have also disseminated original code:
https://github.com/regmdr/HUSH_analysis
3.Enriquez-Gasca R.*, Gould, P.A.* Tunbak, H., Conde, L., Herrero, J., Chittka, A., Beck, C.R. Gifford, R., Rowe, H.M. 2023. Co-option of endogenous retroviruses through genetic escape from TRIM28 repression. Cell Rep 42, 112625.
Here, we shed light on which endogenous retroviruses become repurposed by the host and why.
We disseminated this work as a preprint on bioRxiv before publishing it in Cell Reports and plan to disseminate our original molecular reagents and pipelines where requested.
These discoveries and their international dissemination and exploitation were made possible through this ERC starting grant. We also benefited from key collaborations at UCL (Prof Javier Herrero), the Francis Crick Institute (Prof George Kassiotis), the EPFL in Switzerland (Prof Didier Trono) and Glasgow University (Dr Robert Gifford). We thank the high performance computing clusters at UCL and at QMUL for supporting our computational analyses of high throughput sequencing data and all lab facilities, including the genome centre at QMUL.