Understanding chromosome structure in health and disease
Supervisor: Professor Nick Gilbert
Chromatin is organised non-randomly in the nucleus. Subnuclear structures like the nucleolus, nuclear envelope, and other nuclear bodies, together with chromatin-associated protein complexes and chromatin-associated RNAs (caRNA) control the spatial organisation of chromosomes in three-dimensional (3D) space of the nucleus. Newly transcribed RNA also interacts with proteins such as HNRNPU (also called Scaffold-Attachment-Factor-A) to form a nucleoprotein gel that maintains structural stability of the genome. Through this process the HNRNPU/RNA gel decompacts chromatin and in its absence there is a radical change in chromosome structure. Abnormal spatial organisation of DNA is linked to many diseases like cancer, Huntington’s disease, progeria, and metabolic syndromes. Recently, mutations in HNRNPU have been linked to diseases with phenotypes including intellectual disability, autism spectrum disorder, and seizures. Interstingly, the effect of genome organisation and other nuclear processes in these diseases is not yet understood. Our hypothesis suggests that chromatin 3D mis-regulation disrupts normal nuclear processes such as gene expression and RNA export, leading to the disease phenotype. To test this hypothesis we will investigate the function of HNRNPU using biochemistry and molecular biology techniques in healthy cells and mutate the protein to understand how it functions in human disease.
Nozawa RS et al SAF-A Regulates Interphase Chromosome Structure through Oligomerization with Chromatin-Associated RNAs. Cell. 2017, 169(7):1214-1227.
Nozawa RS, Gilbert N. RNA: Nuclear Glue for Folding the Genome. Trends Cell Biol. 2019, 29(3):201-211.
Marenda M, Lazarova E, Gilbert N. The role of SAF-A/hnRNP U in regulating chromatin structure. Curr Opin Genet Dev. 2022, 72:38-44.