RNA

I read an article recently about an anti-vaccination advocate exclaiming at a press conference with the governor of Florida that vaccines against SARS-CoV-2 “change your RNA!” This made me think that most people probably do not know much about RNA and that a little knowledge is a dangerous thing. Now ironically, contrary to what the newspapers say, this statement is kind of true although in a trivial way. The Moderna and Pfizer vaccines insert a little piece of RNA into your cells (or rather cells ingest them) and that RNA gets translated into a SARS-CoV-2 spike protein that gets expressed on the surface of the cells and thereby presented to the immune system. So, yes these particular vaccines (although not all) have changed your RNA by adding new RNA to your cells. However, I don’t think this is what the alarmist was worried about. To claim that something that changes is a bad thing implies that the something is fixed and stable to start with, which is profoundly untrue about RNA.

The central dogma of molecular biology is that genetic information flows from DNA to RNA to proteins. All of your genetic material starts as DNA organized in 23 pairs of chromosomes. Your cells will under various conditions transcribe this DNA into RNA, which is then translated into proteins. The biological machinery that does all of this is extremely complex and not fully understood and part of my research is trying to understand this better. What we do know is that transcription is an extremely noisy and imprecise process at all levels. The molecular steps that transcribe DNA to RNA are stochastic. High resolution images of genes in the process of transcription show that transcription occurs in random bursts. RNA is very short-lived, lasting between minutes to at most a few days. There is machinery in the cell dedicated to degrading RNA. RNA is spliced; it is cut up into pieces and reassembled all the time and this splicing happens more or less randomly. Less than 2% of your DNA codes for proteins but virtually all of the DNA including noncoding parts are continuously being transcribed into small RNA fragments. Your cell is constantly littered with random stray pieces of RNA, and only a small fraction of it gets translated into proteins. Your RNA changes. All. The. Time.

Now, a more plausible alarmist statement (although still untrue) would be to say that vaccines change your DNA, which could be a bad thing. Cancer after all involves DNA mutations. There are viruses (retroviruses) that insert a copy of its RNA code into the host’s DNA. HIV does this for example. In fact, a substantial fraction of the human genome is comprised of viral genetic material. Changing proteins can also be very bad. Prion diseases are basically due to misfolded proteins. So DNA changing is not good, protein changing is not good, but RNA changing? Nothing to see here.

New paper in eLife

I never thought this would ever be finished but it’s out. We hedge in the paper but my bet is that MYC is a facilitator of an accelerator essential for gene transcription.

Dissecting transcriptional amplification by MYC

eLife 2020;9:e52483 doi: 10.7554/eLife.52483

Zuqin Nie, Chunhua Guo, Subhendu K Das, Carson C Chow, Eric Batchelor, S Stoney Simons Jr, David Levens

Abstract

Supraphysiological MYC levels are oncogenic. Originally considered a typical transcription factor recruited to E-boxes (CACGTG), another theory posits MYC a global amplifier increasing output at all active promoters. Both models rest on large-scale genome-wide ”-omics’. Because the assumptions, statistical parameter and model choice dictates the ‘-omic’ results, whether MYC is a general or specific transcription factor remains controversial. Therefore, an orthogonal series of experiments interrogated MYC’s effect on the expression of synthetic reporters. Dose-dependently, MYC increased output at minimal promoters with or without an E-box. Driving minimal promoters with exogenous (glucocorticoid receptor) or synthetic transcription factors made expression more MYC-responsive, effectively increasing MYC-amplifier gain. Mutations of conserved MYC-Box regions I and II impaired amplification, whereas MYC-box III mutations delivered higher reporter output indicating that MBIII limits over-amplification. Kinetic theory and experiments indicate that MYC activates at least two steps in the transcription-cycle to explain the non-linear amplification of transcription that is essential for global, supraphysiological transcription in cancer.