title: The cancer-associated CTCFL/BORIS protein targets multiple classes of genomic repeats, with a distinct binding and functional preference for humanoid-specific SVA transposable elements.
abstract: BACKGROUND
  A common aberration in cancer is the activation of germline-specific proteins. The DNA-binding proteins among them could generate novel chromatin states, not found in normal cells. The germline-specific transcription factor BORIS/CTCFL, a paralog of chromatin architecture protein CTCF, is often erroneously activated in cancers and rewires the epigenome for the germline-like transcription program. Another common feature of malignancies is the changed expression and epigenetic states of genomic repeats, which could alter the transcription of neighboring genes and cause somatic mutations upon transposition. The role of BORIS in transposable elements and other repeats has never been assessed.
  
  
  RESULTS
  The investigation of BORIS and CTCF binding to DNA repeats in the K562 cancer cells dependent on BORIS for self-renewal by ChIP-chip and ChIP-seq revealed three classes of occupancy by these proteins: elements cohabited by BORIS and CTCF, CTCF-only bound, or BORIS-only bound. The CTCF-only enrichment is characteristic for evolutionary old and inactive repeat classes, while BORIS and CTCF co-binding predominately occurs at uncharacterized tandem repeats. These repeats form staggered cluster binding sites, which are a prerequisite for CTCF and BORIS co-binding. At the same time, BORIS preferentially occupies a specific subset of the evolutionary young, transcribed, and mobile genomic repeat family, SVA. Unlike CTCF, BORIS prominently binds to the VNTR region of the SVA repeats in vivo. This suggests a role of BORIS in SVA expression regulation. RNA-seq analysis indicates that BORIS largely serves as a repressor of SVA expression, alongside DNA and histone methylation, with the exception of promoter capture by SVA.
  
  
  CONCLUSIONS
  Thus, BORIS directly binds to, and regulates SVA repeats, which are essentially movable CpG islands, via clusters of BORIS binding sites. This finding uncovers a new function of the global germline-specific transcriptional regulator BORIS in regulating and repressing the newest class of transposable elements that are actively transposed in human genome when activated. This function of BORIS in cancer cells is likely a reflection of its roles in the germline.
authors: Laboratory of Immunogenetics, NIH, NIAID, Rockville, MD 20852 USA.
authors: Elena M
authors: EM
authors: Pugacheva
authors: Molecular Epigenetics Laboratory, Guangzhou Institutes of Biomedicine and Health, Guangzhou, 510530 Guangdong China.
authors: Evgeny
authors: E
authors: Teplyakov
authors: Molecular Epigenetics Laboratory, Guangzhou Institutes of Biomedicine and Health, Guangzhou, 510530 Guangdong China.
authors: Qiongfang
authors: Q
authors: Wu
authors: Molecular Epigenetics Laboratory, Guangzhou Institutes of Biomedicine and Health, Guangzhou, 510530 Guangdong China.
authors: Jingjing
authors: J
authors: Li
authors: Molecular Epigenetics Laboratory, Guangzhou Institutes of Biomedicine and Health, Guangzhou, 510530 Guangdong China.
authors: Cheng
authors: C
authors: Chen
authors: Molecular Epigenetics Laboratory, Guangzhou Institutes of Biomedicine and Health, Guangzhou, 510530 Guangdong China.
authors: Chengcheng
authors: C
authors: Meng
authors: Molecular Epigenetics Laboratory, Guangzhou Institutes of Biomedicine and Health, Guangzhou, 510530 Guangdong China.
authors: Jian
authors: J
authors: Liu
authors: Laboratory of Immunogenetics, NIH, NIAID, Rockville, MD 20852 USA.
authors: Susan
authors: S
authors: Robinson
authors: Laboratory of Immunogenetics, NIH, NIAID, Rockville, MD 20852 USA.
authors: Dmitry
authors: D
authors: Loukinov
authors: Molecular Epigenetics Laboratory, Guangzhou Institutes of Biomedicine and Health, Guangzhou, 510530 Guangdong China.
authors: Abdelhalim
authors: A
authors: Boukaba
authors: Department of Biology, Southern University of Science and Technology of China, Shenzhen, 518055 Guangdong China.
authors: Andrew Paul
authors: AP
authors: Hutchins
authors: Laboratory of Immunogenetics, NIH, NIAID, Rockville, MD 20852 USA.
authors: Victor
authors: V
authors: Lobanenkov
authors: Molecular Epigenetics Laboratory, Guangzhou Institutes of Biomedicine and Health, Guangzhou, 510530 Guangdong China.
authors: Alexander
authors: 0000-0002-9058-2256
authors: A
authors: Strunnikov