Epigenetic control of neurodevelopmental gene regulatory networks linked to neurodegeneration (360G-Wellcome-203850_Z_16_A)

Dementia is predicted to affect 130 million people worldwide by 2050 according to the World Alzheimer 2015 Report30. Some familial forms of dementia inherited in autosomal-dominant fashion are linked to mutations altering gene dosage2,8,14,16,19,23,25. Patients with the mutations display a long pre-symptomatic phase during which cellular changes may take place before the onset of the disease decades later23. The cellular changes are reflected in gene regulatory networks3,4,5,12,28,31. As evidence from other neurodevelopmental conditions suggests10,13,17, changes during early neural development may lead to onset of the disease decades later. In order to study the neurodevelopmental gene regulatory networks and their links to dementia, I would like to focus on two forms of their regulation: small RNAs and demethylation escapees. Demethylation escapees are regions of the genome that escape epigenome resetting during early embryonic development27. Small RNAs have an important role in neural development and gene regulatory networks controlling them1,6,20,24. In order to address the question, I will use RNA and whole genome bisulfite sequencing methods of neurons derived from human stem-cells from familial dementia patients, combined with bioinformatics analyses. Focusing on small RNAs and demethylation escapees, the project might hint at neurodevelopmental gene regulatory pathways dysregulated in autosomal familial dementia.