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Transcription is the primary control point for gene expression. It therefore determines cellular function and cell identity, and must be tightly regulated to achieve a high degree of specificity. Thus, it is not surprising that transcription is subject to regulation at each of its steps — initiation, elongation and termination. Many proteins, RNAs and features of chromatin are involved in these regulatory steps to ensure that, in each cell, the transcriptional machinery is recruited and activated at specific genes, progresses through chromatin at appropriate rates, and terminates in a controlled manner.
This specially commissioned Focus issue highlights the exquisite complexity of transcription regulation. Recent structural information on RNA polymerase II (Pol II) initiation complexes provides insight into the mechanisms by which Pol II binds specific promoters and initiates RNA synthesis. At the genome-wide level, we now have a better understanding of how the selective activation of enhancers drives cell-specific gene expression, how promoter-proximal pausing of Pol II and transcription elongation rates affect gene expression and co-transcriptional processes, and how transcription termination pathways contribute to shaping the transcriptome. Insights have also been gained into the mechanisms that enable transcription-associated histone exchange and chromatin remodelling and into the important functions of the Mediator complex in the regulation of enhancer–promoter gene looping, transcription initiation and elongation.
Transcription of eukaryotic protein-coding genes requires the assembly of a conserved initiation complex at promoter DNA. Structural information on this complex, which comprises RNA polymerase II and the general transcription factors, is beginning to reveal the mechanisms underlying the initial steps of transcription, such as the recognition and opening of promoter DNA.
Many gene expression patterns are dictated by enhancers. Mammalian genomes contain millions of potential enhancers, but only a small subset of them is active in any cell type. Emerging data uncover how cell type-specific enhancer function is established, including the involvement of higher-order genomic organization in the process.
RNA polymerase II (Pol II) is globally regulated by Mediator, a large, conformationally flexible protein complex with a variable subunit composition. These biochemical characteristics are fundamental for the ability of Mediator to control processes involved in transcription, including the organization of chromatin architecture and the regulation of Pol II pre-initiation, initiation, re-initiation, pausing and elongation.
Pausing of RNA polymerase II (Pol II) in promoter-proximal regions and its release to initiate productive elongation are key steps in the regulation of transcription, and involve many factors. Evidence is now emerging that transcriptional elongation is highly dynamic. Elongation rates vary between genes and across the length of a gene, affecting splicing, termination and genome stability.
Access of RNA polymerase II to DNA is regulated by the ordered disassembly of nucleosomes and by histone exchange. Chromatin modifications, chromatin remodellers, histone chaperones and histone variants control nucleosomal dynamics, and dysregulation of these components results in aberrant transcription.
Transcription termination has a central role in regulating gene expression, maintaining the stability of the transcriptome and controlling pervasive transcription. New insights have recently been gained into the molecular basis of termination and the timely and efficient dismantling of elongation complexes at mRNA-coding and non-coding RNA loci.
PRDM16 activates brown adipose-selective genes through direct interaction with the Mediator complex subunit MED1 at enhancer regions and the regulation of chromatin architecture.
Ronald and Joan Conaway highlight studies that established the role of phosphorylation of the RNA polymerase II carboxy-terminal domain (CTD) in the transition from transcription initiation to elongation, which paved the ground for following work on the CTD in regulating co-transcriptional processes.