Nuclear Retention of mRNA in Mammalian Tissues

Abstract

SummarymRNA is thought to predominantly reside in the cytoplasm, where it is translated and eventually degraded. Although nuclear retention of mRNA has a regulatory potential, it is considered extremely rare in mammals. Here, to explore the extent of mRNA retention in metabolic tissues, we combine deep sequencing of nuclear and cytoplasmic RNA fractions with single-molecule transcript imaging in mouse beta cells, liver, and gut. We identify a wide range of protein-coding genes for which the levels of spliced polyadenylated mRNA are higher in the nucleus than in the cytoplasm. These include genes such as the transcription factor ChREBP, Nlrp6, Glucokinase, and Glucagon receptor. We demonstrate that nuclear retention of mRNA can efficiently buffer cytoplasmic transcript levels from noise that emanates from transcriptional bursts. Our study challenges the view that transcripts predominantly reside in the cytoplasm and reveals a role of the nucleus in dampening gene expression noise.

The influence of nuclear compartmentalisation on stochastic dynamics of self-repressing gene expression

“…As is shown in Figure 11, we consider very broad ranges which cover 7 orders of magnitude -this encapsulates experimental estimates of nuclear export rates which are in the range 10 −4 to 10 1 min −1 (Bahar Halpern et al, 2015). Unsurprisingly, decreasing nuclear mRNA export (T 1 ) results in an increase in abundance of nuclear mRNA and increasing nuclear protein import (T 2 ) results in an increase in nuclear protein abundance.…”

“…Additionally, from Figure 5 (b) and (d) we can see that there is an optimal import rate that minimises protein noise for mRNA export rates in the range 10 −3 to 10 1 min −1 . Interestingly, experimentalists have estimated the nuclear export rates to be in the range 10 −4 to 10 1 min −1 (Bahar Halpern et al, 2015), meaning that the import rate is crucial for determining whether or not noise is increased or decreased. By comparing the noise produced by model 3 vs. model 4 (plots (e) and (f)), we can see that the addition of negative feedback to a gene expression model with compartmentalisation can increase mRNA and protein noise if protein import is slow while if protein import is fast then the models produce approximately equal mRNA and protein noise levels.…”

“…It is known that both negative feedback and compartmentalisation can reduce gene expression noise (Savageau, 1974;Becskei and Serrano, 2000;Simpson et al, 2003;Swain, 2004;Boyer et al, 2005;Tao et al, 2007;Singh and Bokes, 2012;Bahar Halpern et al, 2015;Battich et al, 2015). The central question we sought to address in this paper was: what effect does the combination of both negative feedback and compartmentalisation have on gene expression noise?…”

Equivalent high-resolution identification of neuronal cell types with single-nucleus and single-cell RNA-sequencing

“…Moreover, the shape of the distributions of nuclear 175 transcript proportions was highly similar between tissues with slightly higher proportions estimated in this 176 study. These results suggest that the mechanisms regulating the spatial localization of these transcripts -for 177 example, rates of nuclear export and cytoplasmic degradation (Halpern et al 2015) -are conserved across 178 cell types.…”

“…We compared our estimates of nuclear enrichment in cortex to mouse liver and pancreas based on data 173 from (Halpern et al 2015) and found moderately high correlation (r = 0.61) between 4,373 mostly house-…”