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HybReader

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Mechanisms of epigenetic gene regulation by R loops

The last decade has revolutionized our thinking about regulatory RNAs and yet we are still at the beginning of understanding their biology. One such challenge is presented by R-loops, prevalent DNA:RNA hybrids, which lie at the in... see more

30/11/2023

IMB

2M€

Project Budget: 2M€

Project leader

INSTITUT FUR MOLEKULARE BIOLOGIE GGMBH No se ha especificado una descripción o un objeto social para esta compañía.

PARTICIPATION DEPralty Sin fecha límite de participación.

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Financing granted El organismo H2020 notifico la concesión del proyecto The day 2023-11-30

ERC-2017-ADG: ERC Advanced Grant Scope:Objectives

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Cerrada does 7 years

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2 Participantes

IMB

2.00M€ | Leader

FAPERIN

345.45K€ | participant

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Project duration: 66 months Date Start: 2018-05-30
End date: 2023-11-30

Project leader

INSTITUT FUR MOLEKULARE BIOLOGIE GGMBH No se ha especificado una descripción o un objeto social para esta compañía.

Project Budget 2M€

participation deadline Sin fecha límite de participación.

Project description The last decade has revolutionized our thinking about regulatory RNAs and yet we are still at the beginning of understanding their biology. One such challenge is presented by R-loops, prevalent DNA:RNA hybrids, which lie at the interface of different nuclear processes, including transcription, RNA processing, lncRNAs, DNA damage, chromatin, and neurodegenerative disease. Long-time considered a threat to genomic integrity, recent evidence indicates that certain R-loops can act as epigenetic gene regulators. The hypothesis is that nascent RNAs retained at their site of transcription may function as sequence-specific component of mammalian chromatin to shape gene expression. Notably, R-loops found at GC-enriched promoters are implicated in preventing DNA methylation and promote transcription, but how this might occur has remained obscure. In a breakthrough discovery, we identified the first epigenetic R-loop reader. This protein binds directly and specifically to DNA:RNA hybrids in vitro and in vivo, and mediates local DNA hydroxymethylation and demethylation via TET (Ten-Eleven Translocation) cytosine oxidases. Using the R-loop reader as a tool provides a unique entry point to address fundamental questions regarding mechanisms and regulation of the epigenetic function and biological role of these DNA:RNA hybrids. Applying genome-wide approaches and studying the biology of embryonic stem cells (ESCs), we will 1) systematically identify regulatory R-loops, 2) characterize their common features, 3) address how R-loops are decoded in ESC pluripotency and differentiation, 4) investigate how regulatory R-loops are erased, and (5) screen for additional R-loop binders/readers and characterize their epigenetic role. The HybReader project will allow for ground-breaking discoveries regarding the emerging epigenetic function and regulation of these poorly understood regulatory hybrids in the control of gene expression.

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