Research Roundup: July 30, 2021

Connecting early response and later outcome in COVID-19, centenarians' unique microbiomes, T cell exhaustion in cancer, and more

Susanna M. Hamilton
Credit: Susanna M. Hamilton

Welcome to the July 30, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Nosing around the body's initial response to COVID

How the first cells in the body to see SARS-CoV-2 respond may help determine a COVID-19 patient's outcome, according to a new study in Cell. Carly Ziegler, Vincent Miao, institute member Alex Shalek, and associate member José Ordovás-Montañés (all affiliated with the Klarman Cell Observatory) teamed up with Bruce Horwitz (Boston Children's Hospital), Anna Owings and Sarah Glover (University of Mississippi), and others to study the transcriptional profiles of nasal cells collected from newly diagnosed COVID-19 patients and healthy participants. They found that cells from patients who later developed severe disease exhibited muted early antiviral responses. Read more in a Ragon/Broad press release.

Enduring exhaustion

When T cells become exhausted and dysfunctional due to cancer and chronic infections such as hepatitis C and HIV, they also acquire a distinct epigenetic state. Tumor Immunotherapy Discovery Engine (TIDE) project co-leader Kathleen Yates in the Cancer Program, Nicholas Haining (Merck), Debattama Sen (Mass General), and others showed that, in T cells responding to hepatitis C infection, the exhausted state is largely irreversible even after the initial illness has been cured, leading to epigenetic “scarring”. They conclude that T cell exhaustion is a conserved epigenetic state that persists independent of chronic antigen stimulation and inflammation. Reversing exhaustion of T cells therapeutically may require increasing the cells’ epigenetic plasticity. Read more in Nature Immunology.

Undiscovered genetic risk

Although thousands of disease-associated loci have come from genome-wide association studies, many more remain to be found. To explore how to estimate the genetic effect-size distribution of a disease — the number of risk variants, the range of their effect sizes on risk, and sample sizes required to discover them — Schmidt Fellow Luke O’Connor in the Program in Medical and Population Genetics proposes using Fourier Mixture Regression and validates that it accurately estimates real and simulated effect-size distributions. Applied to ten diseases, the approach estimates that between 100,000 and 1 million cases will be required to explain 50 percent of SNP heritability. Read more in Nature Genetics.

How to fight fusion proteins in cancer

Ewing sarcoma is a cancer of the bone and soft tissue around the bone, and a transcription factor fusion, EWS/FLI, is a key driver that is difficult to target therapeutically in this disease. Postdoctoral fellow Bo Kyung Seong, institute member Kim Stegmaier in the Cancer Program, and colleagues used CRISPR-Cas9 screens and found that TRIM8 is an E3 ligase that ubiquitinates and degrades EWS/FLI. They also identified TRIM8 as a selective dependency in Ewing sarcoma. The findings suggest that regulators of fusion oncoproteins, such as TRIM8, could be selective therapeutic targets for Ewing sarcoma and other cancers driven by transcription factor fusions. Read more in Cancer Cell.

A CREative way to study gene regulation

Although more than 900,000 gene-regulating cis-regulatory elements (CREs) have been mapped, their target genes and effects are largely unknown. Steven Reilly, Sagar Gosai, Ryan Tewhey (The Jackson Laboratory), institute member Pardis Sabeti, and colleagues in the Infectious Disease and Microbiome Program developed HCR-FlowFISH, a new method to characterize the function of CRISPRi-disrupted CREs by quantifying the transcription of target genes. They found that CREs can bidirectionally regulate gene expression, regulate multiple genes, and skip over genes to regulate further away. The researchers also investigated the regulatory landscape of the cholesterol level-associated FADS gene cluster, combining CRE-maps with variant reporter assays to identify causal alleles. Read more in Nature Genetics and a Jackson Laboratory story.

Clues to restoring T cell function in cancer

T cells rely on T cell receptors (TCRs) to bind to and destroy cancer cells, but the relationship between TCRs and T cell behavior is not fully understood. Institute member Catherine Wu, Giacomo Oliveira, and colleagues in the Cancer Program used single-cell RNA and TCR sequencing of tumor-invading T cells to study how the structure and function of TCRs correlate to T cell phenotype. They found that most T cells with tumor-specific TCRs bore the molecular signs of "exhaustion," a state of decreased function following chronic antigen exposure that correlates with persistent disease. These findings may help to develop cancer therapies that restore normal T cell function. Learn more in Nature and a Broad story and Dana-Farber video.

Looking at longevity in the gut

Centenarians, or people aged 100 and over, are less susceptible to chronic age-related diseases. In Nature, core institute member Ramnik Xavier of the Infectious Disease and Microbiome Program, Damian Plichta, Hera Vlamakis, and collaborators at the Keio University School of Medicine show that centenarians have a unique microbiome that may help support longevity. By analyzing fecal samples from 160 Japanese centenarians, the team found that compared to younger people, the centenarians showed higher levels of intestinal microbes that produce secondary bile acids such as isoalloLCA, which strongly inhibits the growth of some gram-positive bacteria. The findings could help researchers uncover mechanisms and biomarkers of healthy aging. Read more in a Broad news story.

Metastasis drivers in pancreatic cancer

Cancer metastasis is complex, poorly understood, and particularly relevant for treating pancreatic cancer, as the majority of pancreatic tumors have metastasized by the time they are diagnosed. In Cell Reports, Chao Dai, Jon Rennhack, institute member Bill Hahn of the Cancer Program, and colleagues describe using isogenic cell lines to identify genes regulated by SMAD4, a tumor suppressor gene associated with metastasis. The team then found that FOSL1, a SMAD4 target that is downregulated both in vitro and in vivo, is both necessary and sufficient to drive metastasis to the lungs in mice. These results could provide a target for future therapies of late-stage pancreatic tumors.

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