Research Roundup: February 5, 2021

Welcome to the February 5, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Genetic link between diabetes and fracture risk

Some patients with type 2 diabetes are more prone to fractures, but the reason for this connection has stumped scientists. In Cell Metabolism, institute member Melina Claussnitzer, Nasa Sinnott-Armstrong, Isabel Sousa (Technical University of Munich), Samantha Laber, and colleagues identify a genetic variant that links the two traits together. Using a Variant-to-Function (V2F) framework — which links genetic variants with relevant cells and disease mechanisms — the researchers discovered that a variant connected to both bone density and blood sugar levels suppresses expression of ADCY5, which in turn affects both adipocyte and osteoblast metabolism. This is the first time the framework has uncovered how a single variant affects multiple different traits. Read more in a Broad story.

More than one way to be a cancer gene

The genome harbors many non-canonical open reading frames (ncORFs), which may encode putative proteins. Whether ncORFs reflect truly functional, cancer-relevant entities, has so far been unclear. John Prensner, institute director Todd Golub, and colleagues in the Cancer Program, Genetic Perturbation Platform, Proteomics Platform, Connectivity Map team, and elsewhere studied 553 ncORFs in cell lines. They found that about 50 percent of the ncORFs may produce proteins, and roughly 20 percent influenced gene expression. CRISPR screens revealed that knockout of 57 (~10 percent) affected cancer cells' viability, with one ncORF, which they dub GREP1, emerging as an important vulnerability in breast cancer. Learn more in Nature Biotechnology.

Skin deep

Tissue-resident innate lymphoid cells (ILCs) of a few types help sustain barrier function and signal response. A team including Piotr Bielecki (Yale), Klarman Cell Observatory visiting scientist Samantha Riesenfeld, postdoctoral associates Jan-Christian Hütter and Elena Torlai Triglia, Monika Kowalczyk, core institute member (on leave) Aviv Regev, and Richard Flavell (Yale) used a combination of longitudinal single-cell RNA sequencing, scATAC-seq, in vitro experiments, and in vivo fate mapping in mouse models of psoriasis to characterize skin ILCs and their potential state transitions. The work showed that cells exist in continuously varying states and respond to interleukin-23 by converging on a pathogenic ILC3-like state, highlighting the range and flexibility of skin ILC responses. Read more in Nature.

To learn more about research conducted at the Broad, visit broadinstitute.org/publications, and keep an eye on broadinstitute.org/news.