title: Folate deficiency facilitates recruitment of upstream binding factor to hot spots of DNA double-strand breaks of rRNA genes and promotes its transcription.
abstract: The biogenesis of ribosomes in vivo is an essential process for cellular functions. Transcription of ribosomal RNA (rRNA) genes is the rate-limiting step in ribosome biogenesis controlled by environmental conditions. Here, we investigated the role of folate antagonist on changes of DNA double-strand breaks (DSBs) landscape in mouse embryonic stem cells. A significant DSB enhancement was detected in the genome of these cells and a large majority of these DSBs were found in rRNA genes. Furthermore, spontaneous DSBs in cells under folate deficiency conditions were located exclusively within the rRNA gene units, representing a H3K4me1 hallmark. Enrichment H3K4me1 at the hot spots of DSB regions enhanced the recruitment of upstream binding factor (UBF) to rRNA genes, resulting in the increment of rRNA genes transcription. Supplement of folate resulted in a restored UBF binding across DNA breakage sites of rRNA genes, and normal rRNA gene transcription. In samples from neural tube defects (NTDs) with low folate level, up-regulation of rRNA gene transcription was observed, along with aberrant UBF level. Our results present a new view by which alterations in folate levels affects DNA breakage through epigenetic control leading to the regulation of rRNA gene transcription during the early stage of development.
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing 100020, China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Genesky Biotechnologies Inc, Shanghai 200120, China.
authors.forename: Caihua
authors.initials: C
authors.lastname: Li
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing 100020, China.
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Song
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing 100020, China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Wu
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing 100020, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing 100020, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Department of Laboratory Medicine, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150081, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Pathophysiology, Guangxi Medical University, Guangxi 530021, China.
authors.forename: Kaihui
authors.initials: K
authors.lastname: Yu
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing 100020, China.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Wan
authors.affiliation: Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China.
authors.forename: Jianting
authors.initials: J
authors.lastname: Li
authors.affiliation: Genesky Biotechnologies Inc, Shanghai 200120, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.affiliation: Genesky Biotechnologies Inc, Shanghai 200120, China.
authors.forename: Zebing
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing 100020, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Niu
authors.affiliation: Genesky Biotechnologies Inc, Shanghai 200120, China.
authors.forename: Zhengwen
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing 100020, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D053595:Embryonic Stem Cells / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D005493:Folic Acid Antagonists / Q000633:toxicity; D005494:Folic Acid Deficiency / Q000235:genetics* / Q000378:metabolism; D016193:G1 Phase / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D020459:Genes, rRNA; D006657:Histones / Q000378:metabolism; D002955:Leucovorin / Q000494:pharmacology; D008727:Methotrexate / Q000633:toxicity; D051379:Mice; D009436:Neural Tube Defects / Q000235:genetics / Q000378:metabolism; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D005493:Folic Acid Antagonists; D006657:Histones; D035463:Pol1 Transcription Initiation Complex Proteins; C063844:transcription factor UBF; D002955:Leucovorin; D008727:Methotrexate