Fig. 2. Biology of protein upregulation.

Physical interaction of distal enhancer elements with active gene promoters via chromosomal looping recruits transcription factors, chromatin modifiers, Mediator complex and RNA polymerase II (Pol II), leading to transcription activation. Bidirectional transcription from the promoter region and at enhancers gives rise to non-coding promoter RNAs (pRNAs) and enhancer RNAs (eRNAs), respectively. Natural antisense transcripts (NATs) transcribed from the antisense strand of protein-coding loci, trans-acting long non-coding RNA (lncRNA), pRNAs and eRNAs can scaffold epigenetic modifiers and transcription regulatory proteins at the target gene locus. Alternatively, they can pair directly with complementary regions in mRNA, inducing distinct stimulatory and inhibitory effects on transcription. Nascent pre-mRNA undergoes co-transcriptional and post-transcriptional modification (PTM) such as 5′-capping, 3′-end processing and polyadenylation, alternative splicing, in situ introduction of N⁶-methyladenosine, 5-methylcytosine, N¹-methyladenosine, pseudouridine and 2′-O-methyl modifications and deamination of adenosine to inosine by adenosine deaminases acting on RNA. The resulting mature mRNA isoforms are exported to the cytoplasm through nuclear pores. Translation of mRNA by the ribosome begins at a translation initiation site (TIS) and is regulated by proteins recruited by mRNA structural elements such as an internal ribosome entry site (IRES), and NATs and lncRNAs targeting untranslated regions (UTRs). miRNAs targeting unique sequences in 3′ UTRs can induce mRNA degradation through the RNA interference (RNAi) mechanism. Short upstream open reading frames (uORFs) within the 5′ UTR compete for the ribosome with the productive open reading frame (ORF) that gives rise to the functional full-length protein, thus slowing down its translation. Non-productive transcripts with inclusion of toxic exons characterized by the presence of dysfunctional termination codons are degraded by the nonsense-mediated decay (NMD) pathway. A, activator; R, repressor; Sp, splice-promoting or inhibiting factors.