Research Roundup: January 8, 2021

Base editing for progeria, in situ sequencing, the history of molecular glues, and more

Susanna M. Hamilton
Credit: Susanna M. Hamilton

Welcome to the January 8, 2021 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Base editing successfully treats progeria in mice

Hutchinson-Gilford progeria syndrome is a progressive and fatal genetic disorder caused by a single C-to-T mutation in the gene LMNA. Using a gene editing technology called base editing, a team led by graduate student Luke Koblan, Mike Erdos (NIH), Jonathan Brown (Vanderbilt), Francis Collins (NIH), and Broad core institute member David Liu corrected the mutation in a mouse model of progeria, improving disease symptoms and dramatically increasing the animals' lifespan. The study is one of the first examples of using base editing inside an animal to rescue a serious genetic disease. Find the paper and a related News and Views in Nature, and read more in a Broad news release, a tweetorial from Liu, and coverage in The Wall Street Journal (paywall), NIH Director's Blog, Science, and STAT.

Making better cell line/tumor matches

Cell line- and tumor-based data can be hard to compare in cancer research, as can selecting the right cell line for a study. Computational associate Allison Warren, Cancer Data Science associate director Aviad Tsherniak, data scientist James McFarland, and others in the Cancer Program's Cancer Dependency Map team have developed Celligner, a computational method for aligning cell line and tumor expression profiles. After comparing data from more than 12,000 tumors and 1,200 cell lines, the team found they could measure how well cell lines mimic their relevant tumors, pinpoint opportunities for generating new cell lines, and identify cell lines that may represent specific tumor subpopulations and cell states. Learn more in Nature Communications and a Broad news story.

Studying genomes in their native environment

A team led by graduate students Andrew Payne, Zachary Chiang, and Paul Reginato, associate member Ed Boyden, associate member Jason Buenrostro, and core institute member Fei Chen has developed a new method for simultaneously sequencing and imaging genomes within intact biological samples. This technology, called in situ genome sequencing (IGS), integrates DNA sequencing with microscopy and enables researchers to see exactly how sequences are organized and packed inside cells. In Science, the team describes the new approach and reports the results of testing IGS in human fibroblasts and early mouse embryos. Read more in a news story from the McGovern Institute and tweetorials from Payne and Chiang.

HyPRbolic expression

In PNAS, senior group leader Jamie Marshall, core institute member Fei Chen, Jesse Engreitz (Stanford University), computational associate Ben Doughty, and colleagues in the Kidney Disease Initiative and Lander lab describe a method they developed to sensitively quantify the expression of up to 100 chosen genes in single cells. The approach, Hybridization of Probes to RNA for sequencing (HyPR-seq), is useful for exploring cellular heterogeneity and gene regulation. The method involves hybridizing DNA probes to RNA, distributing cells into nanoliter droplets, amplifying the probes with PCR, and sequencing the amplicons to quantify expression of chosen genes. HyPR-seq reduces costs by up to one hundredfold compared to whole-transcriptome scRNA-seq, making it a powerful method for targeted RNA profiling in single cells.

The mind’s kinds

Synapses subtypes arise from differential patterns of protein expression. Postdoctoral scholar Eric Danielson, Imaging Platform senior director and institute scientist Anne Carpenter, associate member Mark Bathe (MIT), research scientist Karen Perez de Arce, senior computational biologist Beth Cimini, senior group leader Shantanu Singh, and colleagues in the Stanley Center for Psychiatric Research developed a robust approach for unbiased identification of synapse subtypes based on protein expression profiles. Described in eNeuro, the method combines multiplexed fluorescence imaging with advanced image analysis to detect and quantify protein levels using CellProfiler. The team applied the approach to examine synaptic diversity in cultured hippocampal neurons and to examine the molecular events of 100 proteins at excitatory and inhibitory synapses, offering molecular insight into the mechanisms of synaptic plasticity.

Designer degrader

Raghu Vannam (MGH, HMS); Jan Sayilgan (MGH); associate members Christopher Ott and Michael Lawrence of Massachusetts General Hospital Cancer Center, Harvard Medical School, and the Chemical Biology and Therapeutics Science Program (CBTS); and colleagues used in silico modeling to design a new chemical degrader of the enhancer factors CBP/p300, two acetyltransferase paralogues that are critical for the activity of transcriptional enhancers. The new compound, dCBP-1, is highly potent and selective, and can ablate the enhancer that drives oncogenic MYC expression in multiple myeloma. Described in Cell Chemical Biology, dCBP-1 is a useful tool compound for studying enhancer biology in both normal and cancer cells, and may have therapeutic utility in diseases characterized by overactive enhancer activity.

Adapting to cellular stress 

Endoplasmic reticulum (ER) stress in cells causes inflammation across diseases of the colon and liver. Cells respond to ER stress via the unfolded protein response (UPR) by either adapting to ER stress or undergoing programmed cell death. Research scientist Kwontae You of the Klarman Cell Observatory, Aviv Regev (now at Genentech), senior group leader Daniel Graham of the Infectious Disease and Microbiome Program, core institute member Ramnik Xavier, and colleagues used single-cell RNA sequencing to identify transcriptional states associated with the adaptive and terminal UPRs in the mouse intestinal epithelium. The researchers found that QRICH1, a previously uncharacterized protein, was a transcriptional regulator controlling adaptation to ER stress. When analyzing biopsies of patients with liver or colon disease, they found increased QRICH1 transcriptional signature, confirming its role in human disease. Read more in Science.

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