ChemBio seminar by Prof. Marco Di Antonio (Imperial College London, UK) - CH-635
Event details
| Date | 28.11.2023 |
| Hour | 16:15 › 17:15 |
| Speaker | Prof. Marco Di Antonio, Imperial College London, UK |
| Location | |
| Category | Conferences - Seminars |
| Event Language | English |
Title: Long-range G-G base pairing regulates chromatin architecture and promotes RNA condensation in neurodegenerative diseases
Abstract:
Link to PDF
It is well known that the Guanine base can base pair with itself by means of Hoogsteen hydrogen bonding, which can lead to the formation of DNA and RNA secondary structures known as G-quadruplex (G4).1 Whilst G4-formation has been thoroughly investigated within short genomic sequences, G-G base pairing between distal genomic regions have been often overlooked and deemed unlikely to happen in vivo. My group has recently discovered the first human protein (CSB), a chromatin remodelling protein, that can selectively bind to multimolecular G4-structures (mG4s), suggesting that long range G-G base pairing can be potentially leveraged to orchestrate chromatin architecture.2 More recently, my group has demonstrated that the repeat expansion of the hexanucleotide (GGGGCC)n, which has been linked to the neurodegenerative diseases ALS and FTD, can form solid aggregates in a protein independent fashion by means of G-G base pairing. We showed a correlation between the emergence of multimolecular G4s (mG4s) formed by the DNA (GGGGCC)n repeats and the formation of protein free insoluble aggregates. Aggregation is dependent on K+ concentration and repeat-length, indicating that G4-formation is essential to observe aggregates. G4-structures were detected in the aggregates by staining with the G4-specific fluorescent dye NMM. To reinforce the physiological relevance of our observations, we characterised the aggregation of RNA (GGGGCC)n, which is thought to contribute to pathological aggregation in ALS/FTD. We observed that RNA repeats can aggregate at significant lower concentrations compared to DNA, suggesting that under physiological conditions RNA repeats can aggregate in the absence of any protein. Using patient-derived ALS cell lines, we validated our model by observing the same G4-based RNA aggregates in the pathological RNA foci that are characteristic of this disease, suggesting that nucleic acids targeting could be the key to treat neurodegenerative diseases in the future. Our findings constitute the first evidence supporting the formation of multimolecular G4-structures to drive protein-free aggregation in neurodegenerative diseases, challenging the current dogmas on the mechanisms responsible of neurodegeneration and associate protein led aggregate formation.3
Speaker's biography:
Marco Di Antonio obtained his MChem from Pavia University (Italy) in 2007 and his PhD in Molecular Sciences from Padua University (Italy) in 2011. He moved to Cambridge University in 2011 where he worked as a PDRA under the supervision of Prof Sir Shankar Balasubramanian. In 2015 Marco was promoted to Senior Research Associate, before being awarded a BBSRC David Phillips Fellowship to start his own group in 2018.
Marco moved to Imperial College (Chemistry Department) to start his own group in 2018 as a BBSRC research fellow, where he was promoted to Advanced Research Fellow in 2021, as a permanent Lecturer in 2022 and as a Senior Lecturer in 2023. His research group works at the interface between chemistry, biology and genomics, with the aim to develop novel technologies to study cancer and ageing biology from a fresh perspective.
Marco was awarded a Lister Institute Prize in 2022, the Young Investigator Award in Chemical Biology by the International Chemical Society and 2023 and the runner up prize for the Young Investigator in Medicinal Chemistry and Chemical Biology in Academia by EFMC in 2023.
Lab website: https://www.imperial.ac.uk/diantonio-research-group/
Abstract:
Link to PDF
It is well known that the Guanine base can base pair with itself by means of Hoogsteen hydrogen bonding, which can lead to the formation of DNA and RNA secondary structures known as G-quadruplex (G4).1 Whilst G4-formation has been thoroughly investigated within short genomic sequences, G-G base pairing between distal genomic regions have been often overlooked and deemed unlikely to happen in vivo. My group has recently discovered the first human protein (CSB), a chromatin remodelling protein, that can selectively bind to multimolecular G4-structures (mG4s), suggesting that long range G-G base pairing can be potentially leveraged to orchestrate chromatin architecture.2 More recently, my group has demonstrated that the repeat expansion of the hexanucleotide (GGGGCC)n, which has been linked to the neurodegenerative diseases ALS and FTD, can form solid aggregates in a protein independent fashion by means of G-G base pairing. We showed a correlation between the emergence of multimolecular G4s (mG4s) formed by the DNA (GGGGCC)n repeats and the formation of protein free insoluble aggregates. Aggregation is dependent on K+ concentration and repeat-length, indicating that G4-formation is essential to observe aggregates. G4-structures were detected in the aggregates by staining with the G4-specific fluorescent dye NMM. To reinforce the physiological relevance of our observations, we characterised the aggregation of RNA (GGGGCC)n, which is thought to contribute to pathological aggregation in ALS/FTD. We observed that RNA repeats can aggregate at significant lower concentrations compared to DNA, suggesting that under physiological conditions RNA repeats can aggregate in the absence of any protein. Using patient-derived ALS cell lines, we validated our model by observing the same G4-based RNA aggregates in the pathological RNA foci that are characteristic of this disease, suggesting that nucleic acids targeting could be the key to treat neurodegenerative diseases in the future. Our findings constitute the first evidence supporting the formation of multimolecular G4-structures to drive protein-free aggregation in neurodegenerative diseases, challenging the current dogmas on the mechanisms responsible of neurodegeneration and associate protein led aggregate formation.3
Speaker's biography:
Marco Di Antonio obtained his MChem from Pavia University (Italy) in 2007 and his PhD in Molecular Sciences from Padua University (Italy) in 2011. He moved to Cambridge University in 2011 where he worked as a PDRA under the supervision of Prof Sir Shankar Balasubramanian. In 2015 Marco was promoted to Senior Research Associate, before being awarded a BBSRC David Phillips Fellowship to start his own group in 2018.
Marco moved to Imperial College (Chemistry Department) to start his own group in 2018 as a BBSRC research fellow, where he was promoted to Advanced Research Fellow in 2021, as a permanent Lecturer in 2022 and as a Senior Lecturer in 2023. His research group works at the interface between chemistry, biology and genomics, with the aim to develop novel technologies to study cancer and ageing biology from a fresh perspective.
Marco was awarded a Lister Institute Prize in 2022, the Young Investigator Award in Chemical Biology by the International Chemical Society and 2023 and the runner up prize for the Young Investigator in Medicinal Chemistry and Chemical Biology in Academia by EFMC in 2023.
Lab website: https://www.imperial.ac.uk/diantonio-research-group/
Practical information
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