Super-Enhancers at the Nanog Locus Differentially Regulate Neighboring Pluripotency-Associated Genes. Cell Rep 2016 Sep 27;17(1):19-28
Date
09/30/2016Pubmed ID
27681417Pubmed Central ID
PMC5111363DOI
10.1016/j.celrep.2016.09.002Scopus ID
2-s2.0-84989900295 (requires institutional sign-in at Scopus site) 72 CitationsAbstract
Super-enhancers are tissue-specific cis-regulatory elements that drive expression of genes associated with cell identity and malignancy. A cardinal feature of super-enhancers is that they are transcribed to produce enhancer-derived RNAs (eRNAs). It remains unclear whether super-enhancers robustly activate genes in situ and whether their functions are attributable to eRNAs or the DNA element. CRISPR/Cas9 was used to systematically delete three discrete super-enhancers at the Nanog locus in embryonic stem cells, revealing functional differences in Nanog transcriptional regulation. One distal super-enhancer 45 kb upstream of Nanog (-45 enhancer) regulates both nearest neighbor genes, Nanog and Dppa3. Interestingly, eRNAs produced at the -45 enhancer specifically regulate Dppa3 expression by stabilizing looping of the -45 enhancer and Dppa3. Our work illustrates that genomic editing is required to determine enhancer function and points to a method to selectively target a subset of super-enhancer-regulated genes by depleting eRNAs.
Author List
Blinka S, Reimer MH Jr, Pulakanti K, Rao SAuthor
Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCRISPR-Cas Systems
Chromosomal Proteins, Non-Histone
Clustered Regularly Interspaced Short Palindromic Repeats
Endonucleases
Enhancer Elements, Genetic
Gene Editing
Gene Expression Regulation
Human Embryonic Stem Cells
Humans
Mice
NIH 3T3 Cells
Nanog Homeobox Protein
Pluripotent Stem Cells
Primary Cell Culture
Proteins
RNA, Long Noncoding
Transcription, Genetic