Chromatin landscape in transcriptional regulation : A case for ribosomal transcription

Cell survival, growth, and proliferation are dependent on ribosomal protein synthesis. Ribosome biogenesis is thus a highly regulated process to preserve cell function and survival. It is an energy demanding process that needs to be adapted to nutrient availability and other stimuli. The transcription of 45S rRNA, an essential part of the ribosome machinery, serves as the rate-limiting step. The work presented in this thesis focuses on the role of a positive regulator of ribosomal transcription – the B-WICH chromatin remodelling complex. We explore the role it plays in rRNA transcription and delve deeper into its mechanisms. Study I demonstrates that B-WICH is essential to establish and maintain the chromatin accessibility at the rDNA promoter to allow transcription initiation. In the absence of WSTF, a subunit of B-WICH, the ribosomal genes remain inactive and unable to initiate transcription, even upon glucose stimulation. This is because CHD4, as part of NuRD complex, cannot be removed from the promoter thereby rendering it inaccessible. Study II reveals an interaction between WSTF and noncoding RNA IGS38 at the rDNA promoter. In the absence of IGS38, WSTF is not recruited at the promoter which results in chromatin compaction. Subsequently, RRN3 is also not recruited which directly prevents RNA PolI stabilization and thus transcription is blocked. Study III investigates the cellular response to ribosomal transcriptional dysregulation in WSTF deficient cells. We reveal that cells respond in a p53 independent manner, and instead trigger an integrative stress response. Moreover, it affects mitochondrial function and increases reliance on mitochondrial respiration. Thus revealing a different response to B-WICH dependent ribosomal stress. Taken together, these studies establish B-WICH and WSTF at the centre of ribosomal regulation mechanisms. It also demonstrates the important function of chromatin remodelling in essential cellular responses.