Cell culture hood in disarray? Favorite coffee cup missing? Internet running slow? What exactly drives you loopy in the laboratory?! Recently, the lab of Richard A. Young (Whitehead Institute for Biomedical Research, Cambridge, USA) has been driven round the bend in their quest to understand what controls the DNA looping process that brings together enhancers and promoters for gene regulation purposes. Thankfully (for them!), their new findings bring some much-needed harmony that firmly establishes the Yin Yang 1 (YY1) GLI-Kruppel zinc finger transcription factor as a driving force behind the loopy behavior of genes in mammalian cells!
Luckily, Weintraub and colleagues intended to keep us all in the loop:
- Chromatin immunoprecipitation mass spectrometry (ChIP-MS) with antibodies for specific histone modifications (H3K27ac for active enhancers, H3K4me3 for active promoters) first identified YY1 as a potential mediator of DNA looping
- CRISPR cell-essentiality screens and chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) confirmed a role for YY1 in DNA looping
- YY1 is expressed in the majority of tissues and YY1 enhancer/promoter occupation occurs in all cell types examined
- HiChIP analysis (a protein-centric chromatin conformation method) demonstrated that YY1 occupies sites of enhancer-promoter interactions
- YY1 structurally regulates enhancer-promoter interaction by binding to hypomethylated DNA and then preferentially forming YY1 homodimers to generate DNA loops
- YY1-mediated looping facilitates the expression of associated genes
- The process appears similar to CTCF-mediated DNA looping, although CTCF binds to sites distal from enhancers and promoters to form larger loops involved in chromatin insulation
- YY1 mediated enhancer-promoter loops tend to take shape within the larger CTCF-mediated loops
- CRISPR-mediated deletion of YY1 binding sites or depletion of YY1 protein disrupted enhancer-promoter contact and associated gene expression
- Previous reports combined with these findings establish a requirement for YY1 for embryonic and adult cell viability
Overall, the authors suggest that this newly discovered role for YY1 accounts for previously reported diverse functions (including gene expression changes in cancer) and almost certainly represents a general feature of mammalian gene control.
Have you been driven crazy by this exciting new study? Then keep yourself “in the loop” over at Cell, December 2017.