Research Roundup: May 16, 2022

A collection of cell atlases, reactivating aged memory circuits, the case for genetic heart disease risk screening, and more

Susanna M. Hamilton, Broad Communications
Credit: Susanna M. Hamilton, Broad Communications

Welcome to the May 16, 2022 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Cross-tissue cartography

Knowing where genes are active in the body is key to studying and understanding the full range of human diseases. Gökcen Eraslan, Eugene Drokhlyansky, Ayellet Segrè, François Aguet, Orit Rozenblatt-Rosen, Kristin Ardlie, institute member (on leave) Aviv Regev, and others in the Regev lab and GTEx project applied single nucleus methods that can profile myriad cell types, including cells from frozen tissue. Based on data from more than 200,000 cells across multiple tissues, their new atlas revealed unexpected cellular functions and linked some cells to specific diseases for the first time. Appearing in Science, the study is one of four from the Human Cell Atlas that produced complementary cross-tissue cell atlases. Read more in a Broad story, a tweetorial by Eraslan, and stories in Fierce Biotech, US News, and GenomeWeb.

Rebooting the brain's mapping app

The brain's anterior thalamus contains circuits for spatial memory (the memories of our physical surroundings and how to move around them), which wanes as we grow older. In a study published in PNAS, Dheeraj Roy, Ying Zhang (McGovern Institute), institute member Guoping Feng of the Stanley Center for Psychiatric Research, and colleagues show that by stimulating neurons in the anteroventral thalamus of older mice, they could improve animals' ability to complete spatial tasks like running a maze. While the team relied on optogenetics, they hope to find specific, druggable targets for treatments that could reverse spatial memory loss. Learn more in an MIT News story and a tweetorial by Roy.

To understand variants' effects, put them in context

Cells' gene expression patterns are quite dynamic, making it difficult to pin down the precise roles noncoding regulatory DNA variants play in disease. In Nature, Aparna Nathan, institute member Soumya Raychaudhuri of the Program in Medical and Population Genetics (MPG), and colleagues report that single cell studies can show how the effects of such variants — also called expression quantitative trait loci (eQTLs) — depend on cell state, and can reveal complex relationships between state and disease processes. The team studied expression profiles and cell surface markers in ~500,000 memory T cells donated by research subjects from Peru, finding that exploring eQTLs' activity in the proper cell state context is critical for understanding their influence on gene regulation and disease.

Getting to the heart of cardiomyopathy risk

In a new study, Aniruddh Patel, Krishna Aragam, Amit Khera, and others in the Cardiovascular Disease Initiative and MPG explored the frequency of clinically actionable, pathogenic variants implicated in inherited cardiomyopathy among the general population. Using clinical-grade classification of variants identified in over 60,000 participants, they found that approximately 0.7% of study participants harbored one of these variants. These individuals could not be identified using standard cardiac imaging tests, but because of their genetics were at substantial risk of heart failure, abnormal heart rhythms, and death from any cause. Genomic screening at the population level could better identify and allow for risk mitigation in high-risk persons. Read more in JAMA Cardiology and a tweetorial by Khera.

High-efficiency gene delivery tool for neurobiology research

Adeno-associated virus (AAV) vectors are efficient gene delivery tools used for the treatment of a variety of human diseases. In Nature Cardiovascular Disease, Trevor Krolak (Harvard Medical School), Ken Chan, Chenghua Gu (HMS), institute scientist Ben Deverman in the Stanley Center, and colleagues describe AAV-BI30, as a high-efficiency vector to target endothelial cells lining the blood vessels throughout the entire central nervous system (CNS). This AAV is important because previously neurobiology researchers had fewer tools capable of highly selective gene delivery to all segments of the CNS vasculature. The findings from this study confirm that AAV-BI30 is exceptionally well suited to accelerate the understanding of neurovascular biology and help to develop therapeutics to address endothelial dysfunction in neurological disease.

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