Discovery of A noise-regulating pathway

(a functional role for transcriptional noise)

In the 1960s it was hypothesized that organisms might harness intrinsic variability to enable probabilistic bet-hedging decisions between alternate developmental fates, in much the same way that financial houses diversify assets to minimize risk in volatile markets.  However, the equivalent biological diversification mechanisms were not known.  We pioneered the study of HIV’s decision circuit and discovered that stochastic fluctuations (noise) in gene expression act as a genetic switch to drive a fate decision between replication and latency, and is sufficient to establish an on-off switch in the virus.  Our 2005 paper was the first demonstration that noise could drive fate decisions and established the HIV circuit as a canonical example of how noise drives a biological fate decision.  Recently, we reported discovery of an endogenous cellular pathway that amplifies transcriptional noise to potentiate embryonic cell transitions (Desai et al. Science 2021), indicating that noise plays a functional physiological role in cells and can act as a substrate for evolution.

a.     Desai RV, …, Singer RH, Weinberger LS*.  A DNA Repair Pathway Regulates Transcriptional Noise to Control Cell Fate Transitions.  Science (2021) Aug 20;373(6557). PMCID: PMC8667278

b.     Weinberger LS*…, Arkin AP, Schaffer DV.  Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive.  Cell (2005) July 29;122(2):169-82. PMID: 16051143.

c.     Weinberger LS*, Dar RD, Simpson ML. Transient-mediated fate determination in a transcriptional circuit of HIV.  Nature Genetics (2008) Apr;40(4):466-70.  PMID: 18344999 PMC N/A.

d.     Hansen MMK, …, Weinberger, LS*.  Post-Transcriptional Feedback Mechanism for Noise Suppression and Fate Stabilization.  Cell  (2018) Jun 14;173(7):1609-1621.e15. PMCID: PMC6044448.