ACSL1 Is Associated With Fetal Programming of Insulin Sensitivity and Cellular Lipid Content.
Individuals who are born small for gestational age (SGA) have a risk to develop various metabolic diseases during their life course. The biological memory of the prenatal state of growth restricted individuals may be reflected in epigenetic alterations in stem cell populations. Mesenchymal stem cells (MSCs) from the Wharton's jelly of umbilical cord tissue are multipotent, and we generated primary umbilical cord MSC isolates from SGA and normal neonates, which were subsequently differentiated into adipocytes. We established chromatin state maps for histone marks H3K27 acetylation and H3K27 trimethylation and tested whether enrichment of these marks was associated with gene expression changes. After validating gene expression levels for 10 significant chromatin immunoprecipitation sequencing candidate genes, we selected acyl-coenzyme A synthetase 1 (ACSL1) for further investigations due to its key roles in lipid metabolism. The ACSL1 gene was found to be highly associated with histone acetylation in adipocytes differentiated from MSCs with SGA background. In SGA-derived adipocytes, the ACSL1 expression level was also found to be associated with increased lipid loading as well as higher insulin sensitivity. ACSL1 depletion led to changes in expression of candidate genes such as proinflammatory chemokines and down-regulated both, the amount of cellular lipids and glucose uptake. Increased ACSL1, as well as modulated downstream candidate gene expression, may reflect the obese state, as detected in mice fed a high-fat diet. In summary, we believe that ACSL1 is a programmable mediator of insulin sensitivity and cellular lipid content and adipocytes differentiated from Wharton's jelly MSCs recapitulate important physiological characteristics of SGA individuals.
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Roy
R
Joseph
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Jeremie
J
Poschmann
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Rami
R
Sukarieh
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Peh Gek
PG
Too
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Sofi G
SG
Julien
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Feng
F
Xu
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Ai Ling
AL
Teh
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Joanna D
JD
Holbrook
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Kai Lyn
KL
Ng
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Yap Seng
YS
Chong
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Peter D
PD
Gluckman
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Shyam
S
Prabhakar
Singapore Institute for Clinical Sciences (R.J., R.S., P.G.T., S.G.J., F.X., A.L.T., J.D.H., Y.S.C., P.D.G., W.S.), Agency for Science, Technology and Research, Singapore 117609; Genome Institute of Singapore (J.P., S.P.), Agency for Science, Technology and Research, Singapore 138672; Department of Obstetrics and Gynaecology (K.L.N., Y.S.C.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228; and Liggins Institute (P.D.G.), University of Auckland, Auckland 1142, New Zealand.
Walter
W
Stünkel
D000107:Acetylation; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003066:Coenzyme A Ligases / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D044127:Epigenesis, Genetic; D047109:Fetal Development; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D005947:Glucose / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D007328:Insulin / Q000378:metabolism*; D050356:Lipid Metabolism; D008239:Lysine / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008820:Mice, Obese; D020411:Oligonucleotide Array Sequence Analysis
D016207:Cytokines; D006657:Histones; D007328:Insulin; C544400:ACSL1 protein, mouse; D003066:Coenzyme A Ligases; C583414:ACSL1 protein, human; D005947:Glucose; D008239:Lysine