title: A YY1-dependent increase in aerobic metabolism is indispensable for intestinal organogenesis.
abstract: During late gestation, villi extend into the intestinal lumen to dramatically increase the surface area of the intestinal epithelium, preparing the gut for the neonatal diet. Incomplete development of the intestine is the most common gastrointestinal complication in neonates, but the causes are unclear. We provide evidence in mice that Yin Yang 1 (Yy1) is crucial for intestinal villus development. YY1 loss in the developing endoderm had no apparent consequences until late gestation, after which the intestine differentiated poorly and exhibited severely stunted villi. Transcriptome analysis revealed that YY1 is required for mitochondrial gene expression, and ultrastructural analysis confirmed compromised mitochondrial integrity in the mutant intestine. We found increased oxidative phosphorylation gene expression at the onset of villus elongation, suggesting that aerobic respiration might function as a regulator of villus growth. Mitochondrial inhibitors blocked villus growth in a fashion similar to Yy1 loss, thus further linking oxidative phosphorylation with late-gestation intestinal development. Interestingly, we find that necrotizing enterocolitis patients also exhibit decreased expression of oxidative phosphorylation genes. Our study highlights the still unappreciated role of metabolic regulation during organogenesis, and suggests that it might contribute to neonatal gastrointestinal disorders.
authors: Rutgers University, Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), 145 Bevier Road, Piscataway Township, NJ 08854, USA.
authors: Namit
authors: N
authors: Kumar
authors: Rutgers University, Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), 145 Bevier Road, Piscataway Township, NJ 08854, USA.
authors: Manasa
authors: M
authors: Srivillibhuthur
authors: Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors: Shilpy
authors: S
authors: Joshi
authors: Cell and Developmental Biology Department, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Katherine D
authors: KD
authors: Walton
authors: Rutgers University, Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), 145 Bevier Road, Piscataway Township, NJ 08854, USA.
authors: Anbo
authors: A
authors: Zhou
authors: Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
authors: William J
authors: WJ
authors: Faller
authors: Rutgers University, Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), 145 Bevier Road, Piscataway Township, NJ 08854, USA.
authors: Ansu O
authors: AO
authors: Perekatt
authors: Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK.
authors: Owen J
authors: OJ
authors: Sansom
authors: Cell and Developmental Biology Department, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Deborah L
authors: DL
authors: Gumucio
authors: Rutgers University, Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), 145 Bevier Road, Piscataway Township, NJ 08854, USA.
authors: Jinchuan
authors: J
authors: Xing
authors: Department of Biological Sciences, Rutgers, The State University of New Jersey, Newark, NJ 07102, USA.
authors: Edward M
authors: EM
authors: Bonder
authors: Department of Biological Sciences, Rutgers, The State University of New Jersey, Newark, NJ 07102, USA.
authors: Nan
authors: N
authors: Gao
authors: Rutgers Cancer Institute of New Jersey (CINJ), 195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors: Eileen
authors: E
authors: White
authors: Rutgers University, Department of Genetics, Human Genetics Institute of New Jersey (HGINJ), 145 Bevier Road, Piscataway Township, NJ 08854, USA verzi@biology.rutgers.edu.
authors: Michael P
authors: 0000-0003-4082-4330
authors: MP
authors: Verzi
mesh_terms: D000332:Aerobiosis / Q000235:genetics / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D005838:Genotype; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology*; D008297:Male; D051379:Mice; D038081:Organogenesis / Q000235:genetics / Q000502:physiology*; D010085:Oxidative Phosphorylation; D059467:Transcriptome / Q000235:genetics; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D050986:YY1 Transcription Factor; C494699:Yy1 protein, mouse
keywords: Intestinal maturation; Intestinal organogenesis; Mouse; Necrotizing enterocolitis; Oxidative phosphorylation; Villus; YY1