Research Roundup: February 4, 2022

A new brain tumor target, organoids reveal autism biology, molecular crosstalk in the microbiome, and more

Susanna M. Hamilton
Credit: Susanna M. Hamilton

Welcome to the February 4, 2022 installment of Research Roundup, a recurring snapshot of recent studies published by scientists at the Broad Institute and their collaborators.

Treatment targets for childhood brain tumors

Childhood brain tumors are challenging to treat, especially when they’re in the midline structures of the brain like the brain stem or thalamus. In Nature Communications, Prassida Khadka, Zach Reitman (Duke), Cancer Program associate member Mimi Bandopadhayay, institute scientists and Proteomics Platform senior director Steven Carr, Timothy Phoenix (University of Cincinnati), and colleagues investigated key mutations in PPM1D, a gene previously noted in diffuse midline gliomas. They found that PPM1D mutations not only contribute to resistance to radiation treatment, but also help new tumors form. They also identified MDM2, a target of PPM1D, as a promising drug target. Their findings offer clues for the development of future treatments. Learn more in a Broad news story.

Exploring autism risk genes with organoids

Hundreds of genes and loci are associated with autism spectrum disorder, but the mechanisms by which individual mutations affect the brain have remained unclear. In Nature, Bruna Paulsen, Silvia Velasco, Amanda Kedaigle, Martina Pigoni, institute member Paola Arlotta, and colleagues from the Stanley Center for Psychiatric Research, Klarman Cell Observatory, MIT, and the Harvard Department of Stem Cell and Regenerative Biology (HSCRB) show that mutations in three autism risk genes — SUV420H1, ARID1B, and CHD8 — all alter particular neurons' developmental timing, effects that depended on the cells' genomic background. The team came to these findings after studying the three genes in organoid models of the cerebral cortex. Learn more in an HSCRB/Broad news story and tweetorials by Paulsen and Kedaigle.

Racial disparities in COVID-19 vaccine hesitancy and uptake 

To gather data on COVID-19 vaccine hesitancy and uptake, associate member Andrew Chan (MGH) in the Infectious Disease and Microbiome Program (IDMP) and colleagues conducted a study of more than 1.2 million UK and more than 87,000 US participants who used a smartphone app to report vaccine willingness and uptake from March 2020 to February 2021. The team found that in both the US and UK, Black and Hispanic participants reported greater vaccine hesitancy than white participants. Black participants in the US also reported decreased vaccine uptake, but in the UK, there were no statistically significant racial and ethnic disparities in vaccine uptake. These data suggest that the UK may have delivered vaccines in a more equitable manner than in the US. Read more in Nature Communications.

Gut reactions

For Bacteroides, the predominant Gram-negative bacteria of the human intestine, survival depends on the ability of each strain to utilize dietary and host sugars. Sun-Yang Park (Boston Children’s Hospital), IDMP associate member Seth Rakoff-Nahoum at Boston Children’s Hospital, and others showed that a microbial-derived small molecule, butyrate, is a context-dependent inhibitor of Bacteroidales, acting as a fitness-switch that’s dependent on which specific sugar is utilized. Genetic variation in the function and regulation of Acyl-CoA metabolism across Bacteroides species influences butyrate’s inhibitory effects. The work demonstrates the power of bottom-up approaches to reveal forces determining fitness of the microbiome’s members. Read more in Cell.

Redefining genetic diversity in the thalamus

The thalamus, a central structure in the forebrain, is responsible for a wide range of functions from sensory processing to attention and memory. In a review article published in Nature Neuroscience, Dheeraj Roy, institute member Guoping Feng in the Stanley Center, and colleagues synthesize recent research on the unique structure of the thalamus, which gives rise to its various functions. While previous research has pointed to genetically distinct cell populations within the thalamus, modern single-cell profiling suggests that these neurons actually show a gradient of gene expression. The authors propose a new way to describe the functional subunits within the thalamus using gene expression paired with connectivity and computation. 

A new method for analyzing gene sets associated with disease

Identifying classes of genes that are enriched in GWAS data can yield insight into disease. Connecting the single nucleotide polymorphisms identified by GWASs to specific genes, however, can be challenging. In The American Journal of Human Genetics, Katherine Siewert-Rocks, associate member Alkes Price of the Program in Medical and Population Genetics, and colleagues report gene co-regulation score regression (GCSC). Using a framework based on transcriptome-wide association studies, GCSC identifies genes enriched for the heritability of a disease that is explained by the predicted expression of causal genes. The team found that GCSC analyses have higher power than those of some related methods, and identify complementary gene sets. 

A single-cell look at intestinal inflammation

Fibroblasts are cells that provide the framework for tissue structure; they also mediate many cellular processes and can cause the pathological formation of fibrous connective tissue. A team led by Guadalupe Jasso, postdoctoral associate Alok Jaiswal, core institute member Ramnik Xavier of the IDMP, and institute scientist Daniel Graham, director of functional genomics in the IDMP, investigated the relationship between fibroblasts, inflammation, and tissue damage in colon cells to gain a better understanding of inflammatory bowel disease. Single-cell RNA analysis in mice revealed diverse fibroblast populations in mucosal tissues of the gastrointestinal tract, and uncovered molecular circuitries that govern inflammation and tissue remodeling during colitis. Learn more in PLOS Biology.

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