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Understanding the Functional Properties of Enhancers

Abstract

Enhancers are well established and are known to be important genomic regulatory elements, which play an essential role in coding gene transcription regulation. They have a significant impact on multiple epigenetic regulatory events including development and disease. The use of high performance sequencing technologies coupled with bioinformatic analysis has been widely applied in epigenetic research, and many models for enhancer regulatory mechanisms have been proposed and studied. But the research process is still incomplete with many questions remaining. Recently, there has been increasing evidence leading us to believe that in the nuclei, there are multiple layers of epigenetic factors influencing enhancer function in genome-wide effects, such as eRNA expression on enhancers, recruitment of diversified combinatory transcription factors on enhancers, spatial epigenetics, and kinetic epigenetics. In my projects described in Chapter 1, I show that ligand dependent eRNA induction on enhancers is a significant mark of active/ functional enhancers, which affects enhancer targeted coding gene transcription activation. In Chapter 2, I identify one type of unique anti-pause enhancer (A-PEs), JMJD6/BRD4 co-bound enhancers, which regulate their target genes transcription by Polymerase II promoter proximal pause release. This research provided one important example showing that enhancers function by loading combinatory transcription factors biochemical properties assembly. In Chapter 3, I demonstrate that nuclear organization and nuclear local environmental play an important role in regulating gene transcriptional activation. My studies have described that Pit1 (homo- domain transcription factor) bound enhancers require a supportive environment, which is under collaboration with nuclear matrix, matrin-3 to fully function on their targeted gene transcription activation. In Chapter 4, I perform the existence of burst transcription in MCF7 cell system by implementing the method of time-course traveling ratio plots based on using time-course GRO-seq data. This has allowed us to understand the kinetic epigenetic mechanism beneath the cellular multi-steps cyclic regulatory process. I propose that the assembly of combinatory multiple transcription factors is processed kinetically in a time manner to cyclically regulate Pol-II polymerases on their targeted coding gene promoter proximal region from a transiting status among non- productive initiation, pausing, and productive elongation status for transcriptional regulation

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