Saturated fatty acid alters embryonic cortical neurogenesis through modulation of gene expression in neural stem cells |
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| Affiliation: | 1. Department of Biochemistry, College of Medicine and Health Sciences, UAE University, Al Ain, Abu Dhabi, UAE;2. Department of Anatomy, College of Medicine and Health Sciences, UAE University, Al Ain, Abu Dhabi, UAE;1. LADAF, Department of Food and Experimental Nutrition, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Av. Lineu Prestes, 580, B14, 05508-000, Sao Paulo, Brazil;2. Department of Pathology, School of Veterinary Medicine and Animal Sciences, University of Sao Paulo, Av. Prof. Dr. Orlando Marques de Paiva, 87, 05508-270, Sao Paulo, Brazil;3. Department of Clinical Analysis (DSPA), Faculty of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo, Brazil;1. Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, UT, USA;2. Department of Pharmaceutics and Pharmaceutical Chemistry, Salt Lake City, UT, USA;3. Salt Lake Veterans Affairs Medical Center, Salt Lake City, UT, USA;1. Departamento de Ciência de Alimentos, Faculdade de Farmácia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil;2. Ann Romney Center for Neurologic Diseases, Brigham and Women''s Hospital, Harvard Medical School, Boston, MA, USA;3. Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil;4. Department of Biochemistry and Molecular Biology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary;5. Escola de Nutrição e Núcleo de Pesquisa em Biologia, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil;6. Departamento de Morfologia, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil;7. Diabetes and Obesity Research Center, Sanford Burnham Medical Research Institute, Lake Nona, Orlando, FL, USA;8. Departamento de Nutrição, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil;1. Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan;2. Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan;3. Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan;4. Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan |
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| Abstract: | A perturbed maternal metabolic environment such as chronically elevated circulating free fatty acids have been shown to affect stem cell fate during embryonic neurogenesis. However, molecular mechanisms behind this are not well defined, especially in human. Here in using directed differentiation of human embryonic stem cells (hESCs) into cortical neurons as model, we show that chronically elevated saturated fatty acid (palmitate) results in decreased proliferation of neural stem cells and increased differentiation into neurons. This phenotype could be due to palmitate mediated increased expression of key genes needed for neuronal differentiation such as EOMES, TBR1, NEUROD1 and RELN and reduced expression of SREBP regulated lipogenic genes at early stages of cortical differentiation. Furthermore, palmitate treatment increased histone acetylation globally and at select gene promoters among affected genes. We also found differential expression of several lncRNAs associated with cellular stress and metabolic diseases in the presence of palmitate including BDNF-AS suggesting the contribution of additional epigenetic regulatory mechanisms. Together, our results show that saturated fatty acid affects developmental neurogenesis through modulation of gene expression and through epigenetic regulatory mechanisms. |
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