Mapping regulatory networks by chromosome conformation capture in human regulatory T cell — ASN Events
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  2. Poster Session Three
  3. Mapping regulatory networks by chromosome conformation capture in human regulatory T cell

Mapping regulatory networks by chromosome conformation capture in human regulatory T cell (#360)

Tim Sadlon 1 2 , Veronika Bandara 3 , YingYing Wong 3 , Jimmy Breen 2 , Alastair Forrest 4 , Marc Beyer 5 , Joachim Schultze 5 , Simon C Barry 1 2 3
  1. Gastroenterology, WCHN, North Adelaide, SA, Australia
  2. Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia
  3. Paediatrics, University of Adelaide, Adelaide, SA, Australia
  4. Henry Perkins Institute of Medical Research, Perth, WA, Australia
  5. LIMES, University of Bonn, Bonn, Germany

Regulatory T cells (Treg) play a key role in tolerance and immune homeostasis. Treg function and stability is orchestrated by gene networks regulated by FOXP3 and microRNAs. It is now evident that transcriptional regulatory elements such as enhancers often acting over large distances are critical for controlling the cell-type- specific transcription of their target genes. Therefore while genomics datasets can now readily identify functional motifs in chromatin, such as enhancers and bioinformatics can predict transcription factor binding sites with some accuracy, the targets of these regulatory regions frequently cannot be predicted by linear annotation models. We have established chromosome conformation capture assays in order to determine which regulatory elements interact with Treg specific genes, and to superimpose on this our FOXP3 binding site data. This analysis will reveal the conformation dependent transcriptional regulation of Treg genes, and will also facilitate the annotation of SNPs from autoimmune disease risk regions to functional targets. This approach will shed light on the 80% of SNPs that do not disrupt a coding region, and whose targets are currently unknown. As proof of principle we have used SATB1, a key FOXP3 repressed gene in Treg (1), as a conformation capture target. Using 4Cseq we have identified a super-enhancer over 300kb upstream of SATB1 that appears to play a key role in the differential regulation of SATB1 in Treg and T effector cells. We now confirm that this enhancer is T cell activation dependent, is repressed by FOXP3, and overlaps a number of IBD/Colitis SNPs from GWAS datasets, confirming the power of this approach. The functional impact of autoimmune SNPs that map to this region on SATB1 expression is now under investigation.

  1. 1. Beyer M, Thabet Y, Muller RU, Sadlon T, Classen S, Lahl K, et al. Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nature immunology 2011;12(9):898-907.
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