Sirtuins and nuclear receptors in aging and age-associated diseases

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

In the past year, our efforts focus on the role of SIRT1 and/or protein acylation in regulation of embryonic stem cell metabolism, differentiation, and animal development, and the impact of intestinal epithelial glucocorticoid signaling on intestinal inflammation, anti-tumor immunity, and tumorigenesis. Sphingolipids are important structural components of cell membranes and prominent signaling molecules controlling cell growth, differentiation, and apoptosis. Sphingolipids are particularly abundant in the brain, and defects in sphingolipid degradation are associated with several human neurodegenerative diseases. However, molecular mechanisms governing sphingolipid metabolism remain unclear. In a recent study, we report that sphingolipid degradation is under transcriptional control of SIRT1, a highly conserved mammalian NAD+-dependent protein deacetylase, in mouse embryonic stem cells (mESCs). We found that deletion of SIRT1 results in accumulation of sphingomyelin in mESCs, primarily due to reduction of SMPDL3B, a GPI-anchored plasma membrane bound sphingomyelin phosphodiesterase. Mechanistically, SIRT1 regulates transcription of Smpdl3b through c-Myc. Functionally, SIRT1 deficiency-induced accumulation of sphingomyelin increases membrane fluidity and impairs neural differentiation in vitro and in vivo. Our findings discover a key regulatory mechanism for sphingolipid homeostasis and neural differentiation, further imply that pharmacological manipulation of SIRT1-mediated sphingomyelin degradation might be beneficial for treatment of human neurological diseases. A paper describing this study was published in Elife (Fan et al., Elife, 2021). Histone crotonylation is a non-acetyl histone lysine modification that is as widespread as acetylation. Histone crotonylation is derived from crotonyl-CoA, an intermediate metabolite during mitochondrial or peroxisomal fatty acid oxidation as well as lysine and tryptophan metabolism. Biochemically, histone crotonylation can be catalyzed by histone acetyltransferase p300, read by YEATS domain proteins and double PHD fingers, and erased by a number of classically annotated histone deacetylases including SIRT1. However, physiological functions associated with histone crotonylation remain almost completely unknown. In a recent study, we showed that histone crotonylation is crucial for endoderm differentiation of human embryonic stem cells (hESCs). We demonstrate that key crotonyl-CoA producing enzymes are specifically induced in endodermal cells during differentiation of hESCs in vitro and in mouse embryos, where they function to increase histone crotonylation and enhance endodermal gene expression. Consistently, chemical enhancement of histone crotonylation promotes endoderm differentiation of hESCs, whereas deletion of crotonyl-CoA producing enzymes reduces histone crotonylation and impairs meso/endoderm differentiation in vitro and in vivo. Our study uncovers a histone crotonylation-mediated mechanism that promotes endodermal commitment of pluripotent stem cells, which may have important implications in therapeutic strategies against a number of human diseases. A paper describing this study was published in Cell Stem Cell (Fang et al., 2021). Synthetic immunosuppressive glucocorticoids (GCs) are widely used to control inflammatory bowel disease (IBD). However, the impact of GC signaling on intestinal tumorigenesis remains controversial. In collaboration with Dr. John Cidlowski's group at the NIEHS and Dr. Shuang Tang's group at Fudan University Cancer Center, we recently report that intestinal epithelial glucocorticoid receptor (GR), but not whole intestinal tissue GR, promotes chronic intestinal inflammation-associated colorectal cancer in both humans and mice. We showed that in colorectal cancer patients, GR is enriched in intestinal epithelial cells and high epithelial GR is associated with poor prognosis. Consistently, intestinal epithelium-specific deletion of GR (GR iKO) in mice increases macrophage infiltration, improves tissue recovery, and enhances antitumorigenic response in a chronic inflammation-associated colorectal cancer model. Consequently, GR iKO mice develop fewer and less advanced tumors than control mice. Furthermore, oral GC administration in the early-phase of tissue injury delays recovery and accelerates the formation of aggressive colorectal cancers. Our study reveals that intestinal epithelial GR signaling represses acute colitis but promotes chronic inflammation-associated colorectal cancer, and suggests that colorectal epithelial GR could serve as a predictive marker for colorectal cancer risk and prognosis. Our findings further suggest that although synthetic glucocorticoid treatment for IBD should be used with caution in colorectal cancer patients, there is a therapeutic window for glucocorticoid therapy during colorectal cancer development. A manuscript describing this study is currently under revision. In response to COVID-19 pandemic, we initiated two projects to test whether targeting NAD metabolism or inositol phosphate metabolism could regulate anti-viral immunity of immune cells or viral replication in human cells. The inositol phosphate is in collaboration with Dr. Stephen Shears at the NIEHS. Both projects are still ongoing. This project involves research on human coronavirus, novel coronavirus, COVID-19, Severe Acute Respiratory Syndrome coronavirus disease, SARS coronavirus, SARS-coronavirus-2, SARS-cov-2, SARS-cov2, SARS-related coronavirus 2, Severe acute respiratory syndrome coronavirus 2, SARS-Associated Coronavirus, SARS-cov, or SARS-Related Coronavirus.