title: MBD5 regulates iron metabolism via methylation-independent genomic targeting of Fth1 through KAT2A in mice.
abstract: Ferritin plays important roles in iron metabolism and controls iron absorption in the intestine. The ferritin subunits ferritin heavy chain (Fth1) and ferritin light chain (Ftl1) are tightly regulated at both the transcriptional and post-transcriptional levels. However, mechanisms of maintaining stable, basal expression of Fth1 are poorly understood. Here, we show that global deletion of Mbd5 in mice induces an iron overload phenotype. Liver and serum iron levels in Mbd5(-/-) mice were 3·2-fold and 1·5-fold higher respectively, than wild-type littermates; moreover, serum ferritin was increased >5-fold in the Mbd5(-/-) mice. Mbd5 encodes a member of the methyl-CpG binding domain family; however, the precise function of this gene is poorly understood. Here, we found that intestinal Fth1 mRNA levels were decreased in Mbd5(-/-) mice. Loss of Fth1 expression in the intestine could lead to iron over-absorption. Furthermore, deleting Mbd5 specifically in the intestine resulted in a phenotype similar to that of conditional deletion of Fth1 mice. An Fth1 promoter-report luciferase assay indicated that overexpression of Mbd5 enhanced Fth1 transcription in a dose-dependent manner. Histone H4 acetylation of the Fth1 promoter was reduced in the intestine of Mbd5(-/-) mice and further analysis showed that histone acetyltransferase KAT2A was essential for MBD5-induced Fth1 transcription.
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China; Department of Nutrition, School of Public Health, Institute of Nutrition and Food Safety, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Tao
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.forename: Zhuzhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shen
authors.forename: Fudi
authors.initials: F
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D000818:Animals; D001052:Apoferritins / Q000097:blood / Q000235:genetics*; D019175:DNA Methylation; D017353:Gene Deletion; D005786:Gene Expression Regulation; D018390:Gene Targeting; D006432:Hemochromatosis / Q000097:blood / Q000235:genetics / Q000378:metabolism; D064451:Hepcidins / Q000096:biosynthesis; D051548:Histone Acetyltransferases / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D007408:Intestinal Absorption / Q000502:physiology; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D059372:Nucleotide Motifs; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic; D000099224:p300-CBP-Associated Factor
chemical_list: D001052:Apoferritins; D064451:Hepcidins; D051548:Histone Acetyltransferases; D006657:Histones; D007501:Iron; D051783:Methyl-CpG-Binding Protein 2; D012333:RNA, Messenger; C497393:Mecp2 protein, mouse; C000589598:GCN5 histone acetyltransferase, mouse; D000099224:p300-CBP-Associated Factor
keywords: DNA methylation; epigenetic; haemochromatosis; histone acetylation; iron overload