Investigating oscillatory epigenomic mechanisms that mediate metabolic transitions

This thesis is a compilation of the work done towards completion of my doctoral work wherein, using fed-starve cycles as a paradigm, I have elucidated the intricate interplay between microRNA based post-transcriptional mechanisms, transcription and post-translational regulation in the hepatic tissue. These findings have been described in the thesis, which is broadly divided in to 5 chapters. Chapter 1 deals with an extensive literature review with emphasis on two major aspects, viz. various mechanisms/levels of regulation of gene expression and the importance of metabolic flexibility in physiology. Chapter 2 is the compilation of all the materials and methods utilised for the study. Chapter 3 is an elaborate field review on metabolic pathways and regulation of the same in the liver along with our findings on role of oscillatory hepatic-microRNAs in regulating gene expression and physiology during feed-fast cycles. Chapter 4 summarizes the status of the field with respect to regulation of microRNAs and their metabolic functions, along with our findings on nutrient dependent control of transcription and processing of microRNAs in liver. Chapter 5 comprises of literature review on the regulation of global acetylome in metabolic tissues, along with our unpublished findings. In conclusion, we have revealed the importance of molecular changes that are associated with and mediate dynamic physiological alterations such as fed-fast-refed cycles. In addition to providing fundamental insights, the findings have indicated that abrogating some of these oscillatory components, viz fed-microRNAs, could lead to metabolic dysfunctions and aging. By combining omics based discovery approaches and candidate based mechanistic investigations, findings described in my thesis have revealed novel regulatory loops between transcriptional, post-transcriptional and post-translational mechanisms that control protein expression and function. Notably, we have identified that convergent and additive action of a network of miRs orchestrate physiological toggling and are essential for a refed response. Further, by profiling miRnome and acetylome of liver under fed and fast conditions, my work has generated relevant resources for the field. Lastly, these results have generated novel hypothesis vis-à-vis anticipatory mechanisms and systems level changes in the hepatocytes, which orchestrate organism wide physiological transitions.