1. EpEditors David Hanly 29/09/16
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska- Curie grant agreement No

2. Synthetic Epigenomics tools
1: Sequence-specific synthetic histone modifiers
2: Sequence-guided histone modifier inhibitors

3. Sequence guiding
1. Zinc Fingers
2. CRISPR/Cas9

4. Editing
Modifier domains:
DNMT
TET
Modifier inhibitors:
HAT
HDAC

5. Applications Precision tool for histone mark research
EpiPharmaceutical
Anticancer
Epigenetic syndromes

6. 1. Our proposed system - Neuroblastoma

7. 1. Our proposed system - Neuroblastoma
Candidate ncRNA expression
Candidate ncRNA histone methylation

8. 1. Our proposed system - Neuroblastoma
Restore tumour suppressor effect
Improve prognosis

9. 2. Sotos syndrome Irreversible NSD1 loss-of-function NSD1 NSD1 wt mut
Altered histone methylation
Altered target gene expression
Berdasco et al., PNAS 106(51),

10. 2. Sotos syndrome NSD1 target gene Pro-HDACi CRISPR/Cas9 HDAC
Nanoparticle delivery
HDAC
Pro-HDACi
CRISPR/Cas9
NSD1 target gene

11. 2. Sotos syndrome NSD1 target gene Pro-HATi CRISPR/Cas9 HAT Pro-HATi
Nanoparticle delivery
HAT
Pro-HATi
CRISPR/Cas9
NSD1 target gene

12. 2. Sotos syndrome Interrogate developmental pathology
Alleviate symptoms
Pre-birth treatment

13. Epigenetic therapies have limited effectiveness
Why is this important?
Epigenetic therapies have limited effectiveness

14. Novelty Precise targeting of reversible defects
Opens the door to treating “incurable” developmental disorders

15. in epigenomic research
Why care?
Precision
in epigenomic research

16. Why care? Prognosis need (neuroblastoma)
Treatment of rare, incurable disease (Sotos)
Expands the pharmacologically possible

17. Problems and Risks Modifier domain/inhibitor malfunction
Off-target effects
Unknown biological consequences
Ethical uncertainty

18. Solutions In-house evaluation Basic studies
Cell type-specific delivery

19. Why Us?
The Models
The Means
The Collaborations