Folate deficiency facilitates recruitment of upstream binding factor to hot spots of DNA double-strand breaks of rRNA genes and promotes its transcription

Qiu Xie, Caihua Li, Xiaozhen Song, Lihua Wu, Qian Jiang, Zhiyong Qiu, Haiyan Cao, Kaihui Yu, Chunlei Wan, Jianting Li, Feng Yang, Zebing Huang, Bo Niu, Zhengwen Jiang, Ting Zhang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2472-2489
Number of pages18
JournalNucleic acids research
Volume45
Issue number5
DOIs
StatePublished - Mar 17 2017
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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