Extrinsic Noise or Intrinsic Coupling: Dissecting Correlated Fluctuations in Gene Transcription

Understanding stochastic gene transcription requires distinguishing between intrinsic molecular randomness and extrinsic environmental variability. Traditionally, these components are identified as the independent and correlated fluctuations between identical gene copies within the same cell. However, intrinsic gene-gene interactions can introduce additional correlations, challenging this standard approach. Here, we develop a new noise decomposition framework based on a theoretical model of stochastic transcription for an intrinsically coupled gene pair under fluctuating environments. By analytically deriving correlated fluctuations of nascent RNA, we disentangle intrinsic coupling from extrinsic noise based on their distinct relationships with the mean and variance of gene activation probabilities across varying environments. Applying this framework to single-cell transcription data from Drosophila embryos, we uncover previously unidentified couplings between sister alleles and between alternative promoters of an endogenous gene. Our findings offer a versatile approach for deciphering intrinsic gene-gene interactions in stochastic transcription within fluctuating environments.