Document text
Principal Investigator: Xiaoling Li
Organization: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
Fiscal Year: 2021
Award: $3,007,589
Funding agency: National Institute of Environmental Health Sciences
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.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acetylation><Acute><Acylation><Age><Aging><Animals><Apoptosis><Apoptosis Pathway><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Bilayer Fluidity><Biochemical><Body Tissues><Brain><Brain Nervous System><C4HC3 Zinc Finger><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID-19 virus><COVID19><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><COVID19 virus><CV-19><CV19><Cancer Center><Cancer Model><Cancer Prognosis><CancerModel><Cell Body><Cell Communication and Signaling><Cell Function><Cell Process><Cell Signaling><Cell membrane><Cell physiology><Cells><Cellular Expansion><Cellular Function><Cellular Growth><Cellular Metabolic Process><Cellular Physiology><Cellular Process><Chemicals><Chronic><CoA><CoV emergence><CoV-2><CoV2><Coenzyme A><Colitis><Collaborations><Colo-rectal Cancer><Colon or Rectum><Colorectal><Colorectal Cancer><Cues><Cytoplasmic Membrane><Deacetylation><Defect><Degenerative Neurologic Diseases><Degenerative Neurologic Disorders><Development><Disease><Disorder><Dysfunction><E1A Binding Protein p300><EP300><EP300 gene><ES cell><Embryo><Embryonic><Encephalon><Endoderm><Endoderm Cell><Endodermal Cell><Energy Expenditure><Energy Metabolism><Environment><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial><Epithelial Cells><Family><Functional disorder><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Transcription><Genome Stability><Genomic Stability><Glucocorticoid Receptor><Glucocorticoids><Goals><HCoV><HDAC><HDAC Proteins><Histone Deacetylase><Histones><Homeostasis><Human><Immune><Immunes><Impairment><In Vitro><Infiltration><Inflammation><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Inositol Phosphate Metabolism><Inositol Phosphate Metabolism Pathway><Inositol Phosphates><Intermediary Metabolism><Intestinal><Intestines><Intracellular Communication and Signaling><KAT3B><L-Lysine><Link><Lipids><Lysine><Manuscripts><Mediating><Membrane Fluidity><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Mitochondria><Modern Man><Modification><Molecular><Monitor><Murine><Mus><Mφ><NAD-Dependent Protein Deacetylases><NIEHS><National Institute of Environmental Health Sciences><Nervous System Degenerative Diseases><Nervous System Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurologic Disorders><Neurological Disorders><Nuclear Receptors><Nutritional><Oncogenesis><Oral><PHD Finger><PHD Finger Motif><Paper><Pathogenesis><Peptide Domain><Pharmacology><Phase><Physiologic><Physiological><Physiological Homeostasis><Physiology><Physiopathology><Plant Homeodomain Type Zinc Finger><Plasma Membrane><Pluripotent Stem Cells><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Progenitor Cells><Prognosis><Programmed Cell Death><Protein Acetylation><Protein Domains><Protein Modification><Proteins><Publishing><RNA Expression><Receptor Signaling><Recovery><Regulation><Reporting><Research><Role><SARS><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIRT1><SIRT1 gene><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Silent Mating Type Information Regulator 2-like Proteins><Sir2-like Deacetylases><Sir2-like Proteins><Sirtuin 1><Sirtuins><Sphingolipids><Sphingomyelin Cholinephosphohydrolase><Sphingomyelin Cleaving Enzyme><Sphingomyelin Phosphodiesterase><Sphingomyelinase><Sphingomyelinase C><Sphingomyelins><Subcellular Process><Tertiary Protein Structure><Testing><Therapeutic><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Tryptophan Metabolism><Tryptophan Metabolism Pathway><Tumor Immunity><Universities><Virus Replication><Wuhan coronavirus><acyl group><ages><anti-tumor immunity><anti-viral immunity><antitumor immunity><antiviral immunity><biological signal transduction><bowel><c myc><c-myc Genes><cancer immunity><cell component structure><cell growth><cell metabolism><cellular metabaolism><cmyc><colo-rectal><colo-rectal cancer patients><colo-rectal cancer risk><colon cancer patients><colorectal cancer patients><colorectal cancer risk><colorectum><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus emergence><deacylation><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><embryonic stem cell><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><fatty acid oxidation><gut inflammation><hCoV19><hESC><histone acetyltransferase p300><human CoV><human ES cell><human ESC><human corona virus><human coronavirus><human disease><human embryonic stem cell><improved><in vivo><inflammatory disease of the intestine><inflammatory disorder of the intestine><injury to tissue><intestinal autoinflammation><intestinal epithelium><intestinal inflammation><intestinal tumorigenesis><macrophage><mitochondrial><nCoV><nCoV2><nervous system disorder><neural><neurodegenerative illness><neurological disease><new CoV><new corona virus><new coronavirus><novel CoV><novel corona virus><novel coronavirus><nutritious><p300><pathophysiology><plasmalemma><predictive biomarkers><predictive marker><predictive molecular biomarker><relating to nervous system><response><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome-CoV><social role><stem cell of embryonic origin><stem cells><tissue injury><transcription factor><tumor><tumorigenesis><v-myc Avian Myelocytomatosis Viral Oncogene Cellular Homolog><viral multiplication><viral replication><virus multiplication>