Valeriya’s and Helen’s paper is out!

We are very happy that the story of our two prominent alumni, Valeriya (Lera) Malysheva and Helen Ray-Jones, is finally out at Nature Genetics.

We used low-input Capture Hi-C to profile promoter-anchored chromosomal interactions in Type 3 innate lymphoid cells (ILC3s) - rare tissue-resident lymphocytes that lack antigen receptors and regulate barrier immunity.

We then used these 3D maps to reveal ILC3 regulatory architecture and link immune GWAS variants to target genes implicating this cell type. We show that many prioritised genes have a role in ILC3 inflammatory function.

Surprisingly, one of the genes we prioritised for Crohn's disease was CLN3, a somewhat mysterious lysosomal gene that causes the neurodegenerative Batten disease. We show that CLN3 overexpression, but not knockout, in an ILC3-like cell line affects their cytokine secretion and inflammatory gene expression.

In addition to the ILC3-focused story, our paper presents methods that made this analysis possible: multiCOGS, a multivariate extension of our COGS gene prioritisation pipeline and ABCC, Capture Hi-C-adapted ABC. Finally, while we used our low-input Capture Hi-C technique in earlier work, this project is the first to really showcase its power in profiling rare cell types.

The paper was borne out of a close collaboration between our team with Chris Wallace in Cambridge; Nora Lakes, Tareian Cazares, Emily Miraldi and Stephen Waggoner at Cincinnati; Rachel Brown and Eugene Oltz at St Louis; and many others.

This story took a while to come to fruition, and we've encountered a few challenges along the way, from commercial and logistical to scientific (we were in uncharted territory with CLN3 validation!). The interdisciplinary power and determination of our collaborative team is what ultimately brought this story over the line.