Helping deaf mice hear, understanding meiosis mistakes, making sense of TB evolution, and more
Research Roundup: June 5, 2020
Welcome to the June 5, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.
Rescuing genetic deafness in mice
Some genetic hearing loss diseases are caused by recessive mutations in the gene TMC1 that lead to rapid deterioration of hair cells and complete deafness. In Science Translational Medicine, a team led by core institute member David Liu and Jeffrey Holt (Boston Children's Hospital) describes how they used base editing to restore partial hearing to mice with TMC1-related deafness — the first example of genome editing in vivo to fix a recessive sensory loss disorder. Treated mice experienced partially restored hearing and responded to loud sounds. Read more in news releases from Harvard University and Boston Children’s Hospital, and coverage in Genetic Engineering & Biotechnology News.
Sperm in the spotlight
Meiosis generates sperm with highly variable genomes by crossing DNA between parental chromosomes, and sometimes makes mistakes that lead to aneuploidy (having too many or too few chromosomes). To better understand crossovers and aneuploidy, Avery Davis Bell, institute member Steven McCarroll in the Stanley Center for Psychiatric Research, and colleagues developed a new sequencing technique, Sperm-seq, and used it to study meiosis in more than 31,000 sperm cells. They noted patterns in crossover event location, spacing, and number across sperm genomes and donors that suggest a shared underlying regulatory mechanism, and identified many aneuploidies and other genetic abnormalities. Learn more in Nature and in a story from Harvard Medical School.
PTSD genes identified
Understanding which individuals may be susceptible or resilient to post-traumatic stress disorder (PTSD) is vital in the development of effective interventions and treatments. Nikolaos Daskalakis and Karestan Koenen, both associate members in the Stanley Center for Psychiatric Research, Chris Chatzinakos, and collaborators used an approach called transcriptomic imputation to reveal PTSD genetic risk influences on tissue-specific gene expression. The researchers studied 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identified 18 significant associations corresponding to specific tissue-gene pairs. They discovered two PTSD susceptibility genes, ZNF140 and SNRNP35, in European and military European cohorts, respectively. Reporting in Cell Reports, the authors identified SNRNP35, an RNA splicing regulator gene, as the most promising gene for further functional investigation of its role in vulnerability to and resilience against PTSD.
Immunotherapy treatments for cancer don’t work for all patients. Colin Buss (MIT) and institute member Sangeeta Bhatia in the Cancer Program devised a modular nanoparticle system that might help. Their peptide-based nanocomplexes carry oligonucleotides that, in mice, stimulated the immune system and increased the effectiveness of checkpoint inhibitors. The dual treatment halted tumor growth and, in some cases, stopped the growth of tumors elsewhere in the body. Packaging immunostimulants within nanoparticles, in combination with checkpoint inhibitors, could work at much lower doses than is required with unencapsulated immunostimulants. Read more in PNAS and MIT News.
Host of a chance
Mycobacterium tuberculosis (Mtb) infection can manifest in different ways, possibly from varying environmental and immune pressures. A team led by Qingyun Liu, Jianhao Wei, Feng Li, and Qian Gao (Fudan University); Yawei Li and Xuemei Lu (Chinese Academy of Sciences); and associate member Sarah Fortune in the Infectious Disease and Microbiome Program and of the Harvard T.H. Chan School of Public Health sequenced nearly 800 isolates of Mtb from 18 newly diagnosed and treatment-naïve patients. Reporting in Science Advances, the researchers characterized the genetic diversity of Mtb populations at the onset of TB disease and reconstructed the within-host evolution of Mtb. The work suggests that the risk of new drug-resistance mutations varies in a host-dependent fashion.
Mapping the human heart
Single-cell sequencing has advanced our understanding of various organ systems, but in cardiac research, some basic questions have remained, such as the number of cell types in the human heart. Nathan Tucker (now at the Masonic Medical Research Institute), institute member Patrick Ellinor, and colleagues from the Broad-Bayer Precision Cardiology Lab used single-nucleus RNA sequencing to generate the most comprehensive high-resolution cellular map to date of the healthy human heart, identifying new cell types, gene expression patterns across different parts of the organ, and cell types linked to common cardiovascular diseases. Published in Circulation, this work will help scientists decipher how heart cells behave in disease and ultimately enable the identification of novel therapeutic targets in disease-specific cardiac cells. Read more in a Broad story.
CR8ing molecular glue degraders
Molecular glue degraders are drug-like compounds that recruit E3 ubiquitin ligases to target proteins for degradation. Postdoctoral fellow Mikolaj Slabicki, institute member Benjamin Ebert in the Broad Cancer Program, and their colleagues discovered a novel molecular glue degrader, called CR8, by analyzing Drug Repurposing Hub data and looking for compounds that preferentially kill cancer cells with high E3 ubiquitin ligase levels. CR8, a CDK inhibitor, induces binding between CDK12-cyclin K and DDB1, which is part of the E3 ubiquitin ligase complex, resulting in the ubiquitination and degradation of cyclin K. A moiety on CR8 that protrudes from CDK12 confers molecular glue degrader activity. The team suggests that modifying protruding moieties can transform certain compounds into molecular glue degraders. Read more in Nature and in a Broad story.