Super enhancers in the human IgH locus: roles of NF-kB and CTCF

Authors

• FC Mills
• H Xu
• RB Bernstein
• EE Max

Abstract

Large genetic elements, designated Super Enhancers (SE), control cell fate. In this context, we have studied the 3’ Regulatory Regions (3’RR) downstream of both the 5’ (A1) and 3’(A2 duplicated segments of the human IgH constant region locus. In mouse, the 3’RR is a SE and is critical for IgH class switching. ChIP seq for Mediator and acetylated H3 histone enrichment in Ramos 2G6, a human B cell model for switching, indicates the human 3’ RR are Super Enhancers. ChIP seq also defines clustered CTCF sites at the 3’ borders of the SE contain that may mediate chromatin looping in the IgH locus. Because classical and non-classical NF-kB pathways are central to CD40L induction of switching, we are evaluating the role of NF-kB in IgH SE function. Our ChIP seq data for unstimulated Ramos 2G6 shows modest NF-kB enrichment across the IgH locus. However, published IgH locus ChIP seq data shows stronger enrichment for all five NF-kB subunits in GM 12878 cells (activated classical and non-classical pathways). Similarly, our ChIP seq data for the U266 myeloma (non-classical pathway activation) shows robust Rel-B binding in the SE. Therefore, we are performing ChIP seq on Ramos 2G6 stimulated with CD40L and IL-4 to assess the role of NF-kB enrichment in the IgH SE, and in parallel are evaluating NF-kB dependence of enhancer activity across the SE. Finally, these data provide a unique opportunity to understand NF-kB dependent remodeling of the SE landscape in B cells.

Scientific Focus Area: Chromosome Biology

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