Readthrough transcription: How are DoGs made and what do they do?

Abstract

In recent years, the realization that most of the genome is transcribed has transformed the study of mammalian gene expression. Much effort has gone into investigating how this pervasive transcription is regulated and what the functions of the resulting transcripts are, if any. We recently discovered that stress-induced transcriptional readthrough generates very long downstream of gene containing transcripts (DoGs), which may explain up to 20% of intergenic transcription. DoGs are induced by osmotic stress at the level of transcription by a mechanism that depends on calcium release from the endoplasmic reticulum mediated by IP3 receptors. Here, we discuss DoG induction and function in the context of the literature, with special focus on 2 outstanding questions. First, we discuss possible molecular mechanisms underlying DoG induction through reduced transcription termination. Second, we explore how DoGs may function in maintaining euchromatin after nuclear scaffold stress. In short, we review important aspects of DoG biogenesis and function, and provide an outlook for continued DoG study.

Keywords: DoG; redthrough transcription; transcription termination.

Figure 1.

Factors that may affect transcription termination efficiency. 1) Histone acetylation and 2) other chromatin modifications can affect Pol II elongation rate. As Pol II pausing is associated with transcription termination, Pol II elongation rate may affect the efficiency of termination. Further, modification of 3) factors involved in cleavage and polyadenylation or in downstream events, and 4) Pol II itself could affect the efficiency of transcription termination.

Figure 2.

Model for putative DoG function. After exposure to stress – including osmotic stress – the nuclear scaffold is compromised due to stress sensitivity of its protein constituents, and DoGs are induced as reinforcement. The upper-left panel depicts an unstressed nucleus. The upper-right panel depicts a hypothetical nucleus that lacks DoG induction in response to stress: the nuclear scaffold is weakened, the nucleus shrinks and the chromatin condenses. The lower-left panel depicts a stressed nucleus with DoG induction: the DoGs reinforce the nuclear scaffold, resulting in the maintenance of euchromatin and nuclear size.