Research Roundup: December 4, 2020

Welcome to the December 4, 2020 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

New tool helps study autism risk genes 

Typically, understanding the roles of disease genes requires in-depth studies of each gene. A team co-led by Xin Jin, Sean Simmons, Amy Guo, Ashwin Shetty, Lan Nguyen, institute member Elise Robinson of the Stanley Center for Psychiatric Research, senior group leader Joshua Levin of the Klarman Cell Observatory, institute member Paola Arlotta (also in the Stanley Center), core institute member Feng Zhang, and former core institute member Aviv Regev (now at Genentech) used Perturb-Seq, a gene-editing and single cell-sequencing system, to study the function of 35 genes implicated in autism spectrum disorders (ASDs) in many different cell types at once, in vivo in developing mouse brains. With this method, the authors identified networks of gene expression in neuronal and glial cells suggesting new functions in ASD-related genes. Read more in Science and this Harvard story.

BAF mutation linked to developmental disorder

Some mutations in chromatin-remodelling SWI-SNF (or BAF) complexes are associated with rare neurodevelopmental and intellectual disability disorders. Brittany Michel, Nazar Mashtalir, institute member and Epigenomics Program co-director Cigall Kadoch, and colleagues have found that rare variants in BICRA, which encodes an ncBAF complex subunit, are associated with similar disorders. The team identified 12 individuals with these rare variants who have developmental delay and other features linked with other BAF complex-associated intellectual disability disorders. In zebrafish, a mutation in a BICRA ortholog mimics some human phenotypes. Read more in the American Journal of Human Genetics. 

A new dimension for diabetes drug development

One obstacle to developing treatments that trigger pancreatic beta cell regrowth in type 1 diabetes (T1D) is a lack of high-fidelity cell culture systems. Writing in Science Advances, Kisuk Yang, Miseon Lee, Peter Jones (BWH), associate members Amit Choudhary and Jeffrey Karp of the Chemical Biology and Therapeutics Science Program and Brigham and Women's Hospital (BWH), and colleagues present the Disque Platform (DP), a system that aggregates stem cell-derived beta cells into thin 3D disks within 2D culture plates, thereby combining the advantages of 2D and 3D systems. Learn more in a Choudhary Lab tweetorial about how DP is helping them in their efforts to develop zinc-based prodrugs for T1D.

Keeping Cas9 from hanging around

If Cas9 remains active in a cell for too long, it can cause a variety of undesired outcomes, highlighting a need for ways to control its lifespan. Vedagopuram Sreekanth, Qingxuan Zhou, Praveen Kokkonda, Choudhary, and colleagues have engineered a chemogenetic approach called a degradation tag system (dTAG) that brings Cas9 close to a ubiquitin ligase, which flags the Cas enzyme for degradation by the cell's proteasome. By regulating how long Cas9 lingers, dTAG allowed the team to fine tune gene editing outcomes and reduce off-target effects. Learn more in ACS Central Science.

New genetic drivers revealed in melanoma

Jake Conway, Cancer Program associate member Eliezer Van Allen, and colleagues have revealed new genetic drivers and therapeutic vulnerabilities in the four genomic subtypes of melanoma. They performed harmonized and uniform genomic analyses on expanded melanoma whole-exome sequencing data, and uncovered a complex secondary genomic architecture, including multiple oncogenic drivers not previously known to be involved in the disease. The team discovered distinctly different global genomic properties between four subtypes of the cancer (BRAF, (N)RAS, NF1, and triple wild-type), as well as subtype-specific preferences for secondary driver genes. Their meta-analysis indicates various opportunities for further biological and therapeutic investigation. Read more in Nature Genetics.

IMPACTing diversity in GWAS

Eurocentric genetic studies, and limited knowledge of shared causal variants, have made it difficult to apply polygenic risk scores to other ancestries. Now, Tiffany Amariuta, Kazuyoshi Ishigaki, institute member Soumya Raychaudhuri, and colleagues have created a compendium of 707 cell-type-specific regulatory annotations to analyze 111 complex traits and diseases in European and East Asian populations. Their work, published in Nature Genetics, demonstrates that a previously developed annotation strategy called IMPACT can prioritize alleles. These prioritized alleles, in turn, can improve the comparison of genetic data between populations and trans-ancestry portability of polygenic risk score models using ancestrally unmatched data. This study illustrates the need for more genetic data from understudied populations. 

Mapping regulatory networks

Deciphering the networks that regulate gene expression is key to understanding human biology and disease. A team led by Lin Lin (BWH), supervised by Broad associate member David Gifford and colleagues, now describes a systematic method called HIGAN (high-throughput interrogation of gene-centered activation networks) for uncovering and mapping these networks. The researchers applied this suite of multifaceted genomic approaches in two cell lines to explore how the cancer-related gene APOBEC3B is regulated. Learn more about their findings in Cell Reports.

Immunosuppression gets specific

Therapies that reestablish immune tolerance in an antigen-specific manner would avoid the adverse side effects of the nonspecific immunosuppressants currently used to treat autoimmune disease. Associate member Francisco Quintana in the Immunology Program and BWH, Jessica Kenison (Boston University), and others used a nanoliposome-based platform to induce antigen-specific tolerance by modulating aryl hydrocarbon receptor signaling. Treatment with the nanoliposomes suppressed disease pathology and pathogenic autoimmunity in preclinical multiple sclerosis models. Described in PNAS, the work shows that nanoliposomes engineered to deliver tolerogenic small molecules together with disease-related antigens could be a new approach to managing autoimmune disorders.