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.

Revealing stage-specific expression patterns of long noncoding RNAs along mouse spermatogenesis

“…Moreover, in most cases there was a positive correlation, and both the coding gene and the AS were upregulated. This, in the first place, suggests that the existing permisive, transcription-compatible chromatin state, would facilitate transcription from the other strand [28]. On the other hand, some studies in other tissues have revealed that AS lncRNAs transcription/transcripts can interfere with sense coding transcripts at different levels and in different ways, i.e.…”

“…On the other hand, some studies in other tissues have revealed that AS lncRNAs transcription/transcripts can interfere with sense coding transcripts at different levels and in different ways, i.e. by acting at the initiation of transcription, co-transcriptionally, or post-transcriptionally, and exerting either activating or repressing effects [28,45]. In case at least some of the overlapping AS lncRNAs in testis modulate the expression of their host coding genes, the fact that most pairs are positively co-expressed could suggest a mechanism for regulation.…”

“…Nevertheless, due to their genomic arrangement, it is believed that more frequently they act locally, in cis (e.g. by a sense-AS selfregulatory mechanism) [28,45].…”

“…So far, lncRNAs have been implicated in processes as diverse as the maintenance of pluripotency, embryonic development and organ differentiation, imprinting, organization of cell architecture, and apoptosis, among others. Moreover, several lncRNAs have been related to the development of different diseases, including cancer [20,[26][27][28].…”

Histone chaperone FACT and curaxins: effects on genome structure and function

“…Pervasive cryptic transcription has been detected in multiple types of cancer [90–92] , suggesting that the DNA is more accessible to transcription machinery in tumor cells than it is in normal cells, as expected if the nucleosomal barrier is globally weakened. In this case, the role of FACT in stabilizing and restoring nucleosomes would be critical to allow tumor cells to maintain chromatin.…”