Noise properties of adaptation-conferring biochemical control modules.

A key goal of synthetic biology is to develop functional biochemical modules with network-independent properties. Antithetic integral feedback (AIF) is a recently developed control module in which two control species perfectly annihilate each other's biological activity. The AIF module confers robust perfect adaptation to the steady-state average level of a controlled intracellular component when subjected to sustained perturbations. Recent work has suggested that such robustness comes at the unavoidable price of increased stochastic fluctuations around average levels. We present theoretical results that support and quantify this trade-off for the commonly analyzed AIF variant in the idealized limit with perfect annihilation. However, we also show that this trade-off is a singular limit of the control module: Even minute deviations from perfect adaptation allow systems to achieve effective noise suppression as long as cells can pay the corresponding energetic cost. We further show that a variant of the AIF control module can achieve significant noise suppression even in the idealized limit with perfect adaptation. This atypical configuration may thus be preferable in synthetic biology applications.

Widespread hypertranscription in aggressive human cancers.

Cancers are often defined by the dysregulation of specific transcriptional programs; however, the importance of global transcriptional changes is less understood. Hypertranscription is the genome-wide increase in RNA output. Hypertranscription's prevalence, underlying drivers, and prognostic significance are undefined in primary human cancer. This is due, in part, to limitations of expression profiling methods, which assume equal RNA output between samples. Here, we developed a computational method to directly measure hypertranscription in 7494 human tumors, spanning 31 cancer types. Hypertranscription is ubiquitous across cancer, especially in aggressive disease. It defines patient subgroups with worse survival, even within well-established subtypes. Our data suggest that loss of transcriptional suppression underpins the hypertranscriptional phenotype. Single-cell analysis reveals hypertranscriptional clones, which dominate transcript production regardless of their size. Last, patients with hypertranscribed mutations have improved response to immune checkpoint therapy. Our results provide fundamental insights into gene dysregulation across human cancers and may prove useful in identifying patients who would benefit from novel therapies.