Research Roundup: February 18, 2022

Mapping the brain's vascular cells, understanding immune evasion in tumors, profiling stem cell genomes, and more.

Susanna M. Hamilton
Credit: Susanna M. Hamilton

Welcome to the February 18, 2022 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Single cell atlas of brain vasculature

Francisco Garcia (MIT), Na Sun, Epigenomics Program associate member Manolis Kellis, Myriam Heiman (MIT), and colleagues have performed the first single-cell characterization of the human brain vasculature, using fresh-frozen healthy tissue from brain surgery patients and from post-mortem samples. They captured more than 16,000 nuclei across 11 subtypes, and found expression patterns along the arteriovenous axis, new cell-type specific markers, and human cerebrovasculature-specific expression patterns. They used these signatures to study nearly 4,000 cerebrovascular cells from Huntington’s disease patients, revealing activated innate immune signaling in key cell types and reductions in proteins that help maintain the blood-brain barrier in this disease. Read more in Nature and an MIT News story.

Evasive maneuvers

Immune evasion, often via the immunoinhibitory PD-1/PD-L1 axis, is an important factor in tumor growth. Emily Wheeler, Cancer Program associate member Zuzana Tothova, Stephen Elledge (BWH/HMS), and colleagues investigated the cancer drivers that regulate PD-L1 expression. Using a CRISPR-Cas9 screen targeting a panel of 500 top tumor suppressor genes, the team identified CTCF and multiple cohesin genes as key PD-L1 suppressors. They also found that tumor cells upregulate expression of two additional key immune regulatory molecules, PD-L2 and MHC-I, and described the transcriptional consequences of cohesin loss, including induction of the IFN and NF-kB responses. Their findings have implications for understanding cohesin-mutant tumors' biology and treatment. Learn more in PNAS and a video explainer by Tothova and Dana-Farber. 

DNA + RNA = better predictions of immunotherapy outcomes in melanoma

While immunotherapy with checkpoint inhibitors shows great promise in melanoma, the majority of patients don’t respond to treatment. Sam Freeman, Moshe Sade-Feldman, institute members Nir Hacohen and Gad Getz, and colleagues in the Cell Circuits and Cancer programs and beyond investigated whether models that combine DNA and RNA sequencing data from tumor and immune cells can predict melanoma patients’ overall survival and response to immunotherapy. The team identified both DNA- and RNA-based models that nominate tumor mutational, T cell, and B cell burdens, as well as pairs of immune cell- and tumor cell-expressed genes, as outcome predictors. Read more about the project in Cell Reports Medicine.

With a heavy heart

Depression is an emerging risk factor for cardiovascular disease. A team led by Michael Honigberg and associate member Pradeep Natarajan of Massachusetts General Hospital and the Program in Medical and Population Genetics (MPG) tested the association of depressed mood with polygenic risk scores for heart disease. Using UK Biobank data, they showed that lower frequency of depressed mood is independently associated with decreased risk of coronary artery disease (CAD), type 2 diabetes, and atrial fibrillation across the polygenic risk spectrum, and that frequency of depressed mood can be used to stratify patients’ risk for CAD and type 2 diabetes. Depression’s association with CAD was greater in women compared with men. Read more in Nature Cardiovascular Research.

A closer look at hESCs

Human embryonic stem cell (hESC) lines are widely used in research, but no one has yet systematically genomically characterized the available lines at high resolution. In a study reported in Cell Stem Cell, Florian Merkle, Sulagna Ghosh, institute member Steve McCarroll of the Stanley Center for Psychiatric Research, Kevin Eggan (now at BioMarin), and colleagues studied 143 hESC lines using whole genome sequencing. They found that many lines carry more large structural variations than expected but harbor normal numbers of smaller variants, and that certain lines carry disease-associated mutations that could affect the fate and function of cells differentiated from these lines. Their findings form the basis for a new hESC WGS data portal. Learn more in a tweetorial by Florian.

Tempting T cell fate

T cells become regulatory when their T cell receptors (TCRs) have an intermediate to high affinity for self-peptides presented on the major histocompatibility complex. Until now, few studies have illuminated intrinsic features of TCRs that could influence this interaction and T cell fate. In Nature Immunology, Kaitlyn Lagattuta, Kazuyoshi Ishigaki, institute member Soumya Raychaudhuri of the MPG, and colleagues examined TCR sequences in public datasets. They found that hydrophobicity of CDR3β — a region of the β chain on TCRs that mediates antigen recognition — and certain TRBV genes promote T cell regulatory fate. Using these insights, they developed TiRP, a scoring system for intrinsic regulatory potential of TCRs.

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