Welcome to the October 23, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Timestamping RNA 

Sam Rodriques (MIT), graduate student Linlin Chen, associate member Ed Boyden (MIT), core institute member Fei Chen, and colleagues have developed a way to determine when specific messenger RNAs are produced in cells, allowing scientists to measure gene expression in the same cells at multiple time points. The team added “timestamp” DNA sequences to genes of interest in cultured human cells and used with an engineered version of an enzyme called adenosine deaminase acting on RNA (ADAR2cd) to change adenosine bases in the resulting RNA tags to inosine at a predictable rate. By measuring an RNA's inosine-to-adenosine ratio, the researchers could elucidate when it was first produced. Read more in Nature Biotechnology and a Broad story.

Blind mice no longer

Base editors, a genome editing technology developed in the lab of core institute member and Merkin Institute for Transformative Technologies in Healthcare director David Liu, are versatile molecular machines that can convert A•T base pairs to G•C, or vice versa, without cutting the double helix. Base editors have already proven capable of correcting mutations in mice that impair hearing. In a study reported in Nature Biomedical Engineering, Krzysztof Palczewski (UC Irvine) and colleagues — collaborating with Liu, Gregory Newby, and Wei-Hsi Yeh — used a base editor to restore visual function in a mouse model of Leber congenital amaurosis, an inherited retinal disease that causes blindness. Learn more in a UC Irvine press release.

Feast or famine

A region in chromosome 2 linked to ancient adaptation to milk consumption is also associated with obesity and type 2 diabetes in humans. Lifeng Wang (Harvard), visiting researcher Nasa Sinnott-Armstrong, institute member Pardis Sabeti, senior research associate Alham Saadat, visiting scholar Sophie Strobel, associate member Alex Soukas of Massachusetts General Hospital and Harvard Medical School, institute member Melina Claussnitzer in the Metabolism Program, and Anders Näär (Berkeley) discovered that a microRNA, miR-128-1, in the positively selected region is a crucial metabolic regulator in mammals. Appearing in Cell, the work suggests that miR-128-1 helps program a metabolic switch from energy expenditure to energy storage. Though beneficial during ancient famines, altered expression of miR-128-1 may constitute a modern metabolic maladaptation, making it a potential target for treating metabolic disease.

SHARE-seq sheds light on cell fate decisions

As cells differentiate, the way the chromatin is structured inside the cell nucleus changes. To analyze this information at the single-cell level, a team led by Sai Ma, core institute member Aviv Regev (now at Genentech), and Epigenomics Program associate member Jason Buenrostro developed a scalable approach for measuring both chromatin accessibility and gene expression in the same cell. The researchers used this approach, called SHARE-seq, to explore how chromatin accessibility relates to cell fate decisions in mouse tissues. Computational tools that integrate these and other data types could help scientists better understand how genes are regulated across developing cells or heterogeneous cell types within a tissue. Check out the full story in Cell.

Molecular target for prostate cancer therapeutics

Androgen-deprivation therapies (ADTs), which inhibit the androgen receptor (AR), are among the most common therapeutic approaches for treating prostate cancer. However, patients can develop resistance to ADTs through mechanisms that reactivate the AR pathway. Andre Richters, Shelby Doyle, institute member Angela Koehler in the Cancer Program, and colleagues conducted AR-focused small-molecule microarray assays and identified an inhibitor of cyclin-dependent kinase 9 (CDK9), an AR regulator, as an avenue for prostate cancer treatment. Their findings, published in Cell Chemical Biology, also describe the most selective inhibitors of CDK9 found to date, thus providing compelling preclinical in vitro and in vivo support for CDK9 as a therapeutic target in prostate cancer.

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