This project aims to understand the non-canonical activity of retinoic acid (RA) signaling. These studies will employ embryonic stem (ES) cell culture as the experimental model system. Oct4 (Pou5f1) is the """"""""master regulator"""""""" of pluriopotent stem cells including ES, and its expression level must be maintained within a narrow range to ensure the """"""""stemness"""""""" feature of ES. A constant level of Oct4 expression depends upon promyelocytic leukemia (Pml) protein and a particular nuclear structure called Pml-nuclear body (Pml-NB). Our preliminary data show RA exerts a non-canonical activity that rapidly activates Extracellular signal Regulated Kinase 1/2 (ERK1/2), regulates specific proteins'post-translational modification (PTM) and disrupts Pml-NB with which the Oct4 basal promoter is physically associated. This Pml-NB structure is also important for inter- chromosomal coordination of the Oct4 locus with another key stem cell locus Nanog located on a different chromosome. Therefore, the non-canonical activity of RA disrupts Pml-NB, lowers Oct4 and Nanog expression levels and affects the """"""""stemness"""""""" property of ES. We propose a principal hypothesis that in ES cells, the non- canonical RA-activated ERK1/2 alters specific proteins'PTM and regulates the Pml-NB structure which is critical to coordinated regulation of multiple key genomic loci such as Oct4 and Nanog, and ultimately affects the stem cell fate. We propose two aims to understand these newly identified effects of RA. Specifically, aim 1 will examine the non-canonical activity of RA transmitted, at least partially, through ERK1/2 activation to post- translationally modify specific proteins.
Aim 2 will examine how this activity rapidly affects the sub-nuclear structure Pml-NB to facilitate an environment coordinating multiple gene regulation/chromatin remodeling of multiple loci such as Oct4/Nanog loci in ES cells, thereby affecting stem cell fate. Completion of these studies will allow us to construct a more comprehensive picture of how RA signal can be transmitted, through canonical and non-canonical pathways, to modulate the overall health of the cells including ES cells. Understanding these new mechanisms of action of RA will facilitate the manipulation of these specific RA signaling pathways to improve the efficacy of its application as a therapeutic agent/nutrient, and to minimize its serious toxic effects. These studies will also shed lights on the maintenance of ES cell culture with respect to its extreme sensitivity to RA/vitamin A in the culture medium. Furthermore, this non-canonical RA activity may be a key to """"""""epigenetic"""""""" changes caused by RA applied as a therapeutic agent in diseased conditions.
Retinoic acid (RA), the biologically active form of Vitamin A, is essential for a variety of biological processes. RA functions by primarily regulating target gene expression, but it also augments other biological process through non-canonical activities. The long-term goal of this project is to understand how vitamin A affects health and diseases. The current proposal focuses on the non-canonical effects of vitamin A, in particular with regards to the maintenance of embryonic stem cells.
|Park, Sung Wook; Persaud, Shawna D; Ogokeh, Stanislas et al. (2018) CRABP1 protects the heart from isoproterenol-induced acute and chronic remodeling. J Endocrinol 236:151-165|
|Heisel, Timothy; Montassier, Emmanuel; Johnson, Abigail et al. (2017) High-Fat Diet Changes Fungal Microbiomes and Interkingdom Relationships in the Murine Gut. mSphere 2:|
|Hwang, Cheol Kyu; Wagley, Yadav; Law, Ping-Yee et al. (2017) Phosphorylation of poly(rC) binding protein 1 (PCBP1) contributes to stabilization of mu opioid receptor (MOR) mRNA via interaction with AU-rich element RNA-binding protein 1 (AUF1) and poly A binding protein (PABP). Gene 598:113-130|
|Lin, Yu-Lung; Tsai, Hong-Chieh; Liu, Pei-Yao et al. (2017) Receptor-interacting protein 140 as a co-repressor of Heat Shock Factor 1 regulates neuronal stress response. Cell Death Dis 8:3203|
|Lee, Bomi; Iwaniec, Urszula T; Turner, Russell T et al. (2017) RIP140 in monocytes/macrophages regulates osteoclast differentiation and bone homeostasis. JCI Insight 2:e90517|
|Song, Kyu Young; Choi, Hack Sun; Law, Ping-Yee et al. (2017) Post-Transcriptional Regulation of the Human Mu-Opioid Receptor (MOR) by Morphine-Induced RNA Binding Proteins hnRNP K and PCBP1. J Cell Physiol 232:576-584|
|Lin, Yu-Lung; Persaud, Shawna D; Nhieu, Jennifer et al. (2017) Cellular Retinoic Acid-Binding Protein 1 Modulates Stem Cell Proliferation to Affect Learning and Memory in Male Mice. Endocrinology 158:3004-3014|
|Wagley, Yadav; Law, Ping-Yee; Wei, Li-Na et al. (2017) Epigenetic Activation of ?-Opioid Receptor Gene via Increased Expression and Function of Mitogen- and Stress-Activated Protein Kinase 1. Mol Pharmacol 91:357-372|
|Lee, Bomi; Wu, Cheng-Ying; Lin, Yi-Wei et al. (2016) Synergistic activation of Arg1 gene by retinoic acid and IL-4 involves chromatin remodeling for transcription initiation and elongation coupling. Nucleic Acids Res 44:7568-79|
|Wu, Cheng-Ying; Persaud, Shawna D; Wei, Li-Na (2016) Retinoic Acid Induces Ubiquitination-Resistant RIP140/LSD1 Complex to Fine-Tune Pax6 Gene in Neuronal Differentiation. Stem Cells 34:114-23|
Showing the most recent 10 out of 99 publications