Abstract

Despite the generation of transcriptional differences between nearby related cells being the basis of most differentiation and disease, standard measures of RNA synthesis do not register the origins ofthese differences. Although useful for a sorting of genes to context, bulk techniques measure RNA levels from homogenous population extracts, losing dynamic information from individual cells and portraying transcription as a continuous smooth process. The reality is that transcription is irregular, occurring in “bursts” or “pulses” with ON states interspersed by variable duration OFF states. This appears continuous when averaged over millions of cells, but in individual cells, there is considerable variability, and for most genes, very little activity at any one time. These phenomena have come to light with the advent of technologies for precise detection of RNA in single cells, allowing accurate measurements of RNA number, or RNA emergence at a gene. We would like to understand the mechanistic basis of pulsing, and how it is responsive to signals, developmental, chromatin and nuclear context. We are testing the implications of noisy transcription on the generation of diversity between cells in developmental and clinical contexts.