Mechanisms of Antisense Transcription Initiation with Implications in Gene Expression, Genomic Integrity and Disease Pathogenesis

Abstract

Non-coding antisense transcripts arise from the strand opposite the sense strand. Over 70% of the human genome generates non-coding antisense transcripts while less than 2% of the genome codes for proteins. Antisense transcripts and/or the act of antisense transcription regulate gene expression and genome integrity by interfering with sense transcription and modulating histone modifications or DNA methylation. Hence, they have significant pathological and physiological relevance. Indeed, antisense transcripts were found to be associated with various diseases including cancer, diabetes, cardiac and neurodegenerative disorders, and, thus, have promising potentials for prognostic and diagnostic markers and therapeutic development. However, it is not clearly understood how antisense transcription is initiated and epigenetically regulated. Such knowledge would provide new insights into the regulation of antisense transcription, and hence disease pathogenesis with therapeutic development. The recent studies on antisense transcription initiation and its epigenetic regulation, which are limited, are discussed here. Furthermore, we concisely describe how antisense transcription/transcripts regulate gene expression and genome integrity with implications in disease pathogenesis and therapeutic development.

Keywords: GAL10; NuA4; RNA polymerase II; SAGA; TFIID; antisense transcription; chromatin modification; long non-coding RNA.

Figure 1

Schematic diagram showing GAL10 sense and antisense transcriptions in galactose and dextrose-containing growth media, respectively. Bottom panel: The activator, Gal4, targets the co-activator, SAGA, to the GAL10 upstream activating sequence to enhance the formation of PIC, via the Mediator complex, independent of the TAFs that initiate GAL10 sense transcription a in galactose-containing growth medium [88,89]. The 19S proteasome subcomplex, or 19S RP, enhances the targeting of SAGA to Gal4 independent of the proteolytic activity of the 26S proteasome [97]. Top panel: Reb1 targets NuA4 KAT to the 3′-end of the GAL10 coding sequence (GAL10 3′ORF) for histone H4 acetylation and targeting of RNA polymerase II, via TFIID, to initiate GAL10 antisense transcription in dextrose-containing growth medium [83,84]. PIC—pre-initiation complex; SAGA—Spt-Ada-Gcn5-Acetyltransferase; TBP—TATA-box binding proteins; TAFs—TBP-associated factors; NuA4—Nucleosome acetyltransferase of histone H4; TFIID—Transcription factor IID, a complex of TBPs and a set of TAFs; TFIIB—Transcription factor IIB; and 19S RP—19S regulatory particle.