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Chromatin Association of mRNAs Regulates Expression of Genes Important in Mouse Embryonic Stem Cell Biology


Gene expression involves multiple layers of regulation to change the amount of proteins produced. The complexity of this phenomenon starts in the nucleus, where various cis-regulatory elements near genes can engage in transcriptional regulation by association with transcription factors that often function in diverse combinations to enhance or silence transcription. In addition, chemical modifications of DNA such as methylation can have varying impacts on the rate of transcription. Furthermore, molecular events that occur to a maturing pre-mRNA synthesized by RNA polymerase II, notably 5’ capping, splicing and 3’ end processing, all contribute to the intricacies of gene regulation. Whereas these processes need to successfully occur to a maturing pre-mRNA to make it competent for export, malfunction in any of these steps can compromise the RNA’s nuclear export, often leading to its sequestration in the nucleus. Despite ongoing research in the nuclear retention of various RNAs, including mRNAs, mechanisms and tissue-specific consequences of this surveillance mechanism are poorly understood. This work aims to better our understanding of the molecular mechanisms leading to chromatin association of RNAs, particularly mRNAs, by RNA binding proteins PTBP1 and NXF1. Our work demonstrates that these proteins play key roles in altering gene expression in mouse embryonic stem cells (mESCs) through manipulation of splicing and subcellular localization of their target RNAs. We discovered that these mechanisms can have direct consequences on the biology of the mESCs, affecting their pluripotency and differentiation.

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