YY1 Facilitates Enhancer–Promoter Contacts to Promote Gene Expression

Transcription factors bind to enhancers and promoters at sites of physical contact created by DNA looping to promote gene transcription, but the proteins that facilitate structural interactions between enhancers and promoters remain poorly understood. CTCF is one such DNA binding protein. CTCF–CTCF interactions are associated with the large DNA loops that create topologically associating domains (TAD) that insulate genes and enhancers within the CTCF–CTCF loop from elements outside the loop. In this manner, CTCF–CTCF loops constrain DNA interactions within the loop to facilitate enhancer–promoter interactions. However, CTCF is not present at the majority of enhancer–promoter interactions and is only occasionally directly involved in enhancer–promoter interactions. Weintraub, Li, and colleagues hypothesized that a bridging protein (similar to CTCF) might facilitate enhancer–promoter contacts and identified Yin Yang 1 (YY1), a zinc-finger transcription factor overexpressed in many cancers, as a candidate protein via chromatin immunoprecipitation with mass spectrometry (ChIP-MS). In embryonic stem cells, YY1 occupied active enhancers and promoters, whereas CTCF preferentially occupied insulator elements and dimerized to facilitate DNA looping. YY1 was also enriched at active enhancers and promoters in mammalian cell lines, including in colorectal cancer, hepatocellular carcinoma, T-cell acute lymphoblastic leukemia, and chronic myeloid leukemia cells. These findings suggested that YY1–YY1 interactions may induce enhancer–promoter loop formation. Indeed, YY1 enhanced the rate of DNA ligation in an in vitro circularization assay, indicating that YY1 may directly facilitate DNA interactions. Moreover, deletion of YY1 binding sites reduced the frequency of enhancer–promoter contacts, and depletion of the YY1 protein reduced expression of genes generally occupied by YY1. Collectively, these findings support a direct role for YY1 in facilitating enhancer–promoter interactions that facilitate gene expression in malignant and nonmalignant cells.

Weintraub AS, Li CH, Zamudio AV, Sigova AA, Hannett NM, Day DS, et al. YY1 is a structural regulator of enhancer-promoter loops. Cell 2017;171:1573–88.e28.

• ©2018 American Association for Cancer Research.