Selected Grantee Publications
Canine Models of Charcot-Marie-Tooth: MTMR2, MPZ, and SH3TC2 Variants in Golden Retrievers With Congenital Hypomyelinating Polyneuropathy
Cook et al., Neuromuscular Disorders. 2023.
https://pubmed.ncbi.nlm.nih.gov/37400349/
Both demyelination and hypomyelination of the nervous system are associated with various clinical diseases. Using whole-genome sequencing, researchers determined the genetic underpinnings of congenital hypomyelinating polyneuropathy in canines of both sexes. These variants genetically describe the first peripheral nervous system–exclusive hypomyelinating polyneuropathies in dogs. By testing for these mutations, breeders can prevent the production of affected offspring. Supported by ORIP (K01OD027051, K01OD027058).
Diverse Targets of SMN2-Directed Splicing-Modulating Small Molecule Therapeutics for Spinal Muscular Atrophy
Ottesen et al., Nucleic Acids Research. 2023.
https://academic.oup.com/nar/article/51/12/5948/7110763?login=true
Spinal muscular atrophy (SMA) results from deletions or mutations of the SMN1 gene. SMN2 is a nearly identical copy of SMN1 but cannot compensate for its loss. Manipulation of splicing to restore SMN2 exon 7 inclusion provides a promising therapeutic avenue for SMA, and two small-molecule agents—risdiplam and branaplam—restore body-wide inclusion of the SMN2 exon 7 upon oral administration. In this study, researchers demonstrate the advantages of combined treatments with low doses of risdiplam and branaplam. These findings can be applied to develop the next generation of small‑molecule therapeutics, with a focus on better efficacies and fewer off-target effects. Supported by ORIP (T35OD027967) and NINDS.
SALL1 Enforces Microglia-Specific DNA Binding and Function of SMADs to Establish Microglia Identity
Fixsen et al., Nature Immunology. 2023.
https://doi.org/10.1038/s41590-023-01528-8
Microglia function is thought to play a role in neurodevelopmental, psychiatric, and neurodegenerative diseases. Using knockout mice, investigators explored functional interactions between spalt-like transcription factor 1 (SALL1) and SMAD4, which demonstrated that interactions are mediated by a conserved microglia-specific SALL1 super-enhancer and result in direct activation of regulatory elements. The concerted interactions induce a microglia lineage determining program of gene expression. These findings indicate that expression of SALL1 and associated genes could contribute to phenotypes of aging and neurodegenerative diseases. Supported by ORIP (S10OD026929), NIA, NIMH, and NINDS.
A Comprehensive Drosophila Resource to Identify Key Functional Interactions Between SARS-CoV-2 Factors and Host Proteins
Guichard et al., Cell Reports. 2023.
https://pubmed.ncbi.nlm.nih.gov/37480566/
To address how interactions between SARS-CoV-2 factors and host proteins affect COVID-19 symptoms, including long COVID, and facilitate developing effective therapies against SARS-CoV-2 infections, researchers reported the generation of a comprehensive set of resources, mainly genetic stocks and a human cDNA library, for studying viral–host interactions in Drosophila. Researchers further demonstrated the utility of these resources and showed that the interaction between NSP8, a SARS-CoV-2 factor, and ATE1 arginyltransferase, a host factor, causes actin arginylation and cytoskeleton disorganization, which may be relevant to several pathogenesis processes (e.g., coagulation, cardiac inflammation, fibrosis, neural damage). Supported by ORIP (R24OD028242, R24OD022005, R24OD031447), NIAID, NICHD, NIGMS, and NINDS.
Photoreceptor Disc Incisures Form as an Adaptive Mechanism Ensuring the Completion of Disc Enclosure
Lewis et al., eLife. 2023.
https://elifesciences.org/articles/89160
The first steps of vision take place within a stack of tightly packed disc-shaped membranes, or discs, located in the outer segment compartment of photoreceptor cells. In rod photoreceptors, discs are enclosed inside the outer segment and contain deep indentations in their rims called incisures. This presence of incisures has been documented in several species, yet their role remains elusive. This study demonstrated that incisures are formed only after discs become completely enclosed. At the earliest stage of their formation, discs are not round but rather are highly irregular in shape and resemble expanding lamellipodia. In genetically modified mice and frogs, researchers measuring outer segment protein abundances found that incisure size is determined by the molar ratio between peripherin-2, a disc rim protein critical for the process of disc enclosure, and rhodopsin, the major structural component of disc membranes. High perpherin-2-to-rhodopsin ratio causes an increase in incisure size and structural complexity; low ratio precludes incisure formation. They propose a model whereby normal rods express a modest excess of peripherin-2 over the amount required for complete disc enclosure to ensure that this important step of disc formation is accomplished. Once the disc is enclosed, the excess peripherin-2 incorporates into the rim to form an incisure. Supported by ORIP (P40OD010997, R24OD030008).
Epigenetic Dysregulation From Chromosomal Transit in Micronuclei
Agustinus et al., Nature . 2023.
https://www.nature.com/articles/s41586-023-06084-7
The authors reported a mechanistic link between epigenetic alterations and chromosomal instability induced during their transit in micronuclei, both being hallmarks of advanced and metastatic cancers. It was demonstrated that the landscape of histone post-translational modifications was profoundly changed due to missegregation of mitotic chromosomes, their sequestration in micronuclei and subsequent rupture of the micronuclear envelope. The transcriptional redistribution was attributed to micronuclei’s strong positional bias with increased promoter accessibility. The continuous formation and reincorporation of micronuclei promotes epigenetic reprogramming and heterogeneity in cancer. Supported by ORIP (S10OD030286) and others.
Whole Genome Analysis for 163 gRNAs in Cas9-Edited Mice Reveals Minimal Off-Target Activity
Peterson et al., Communications Biology. 2023.
https://www.nature.com/articles/s42003-023-04974-0
CRISPR/Cas9 genome editing offers potential as a treatment for genetic diseases in humans. Using whole-genome sequencing, investigators assessed the occurrence of Streptococcus pyogenes Cas9–induced off-target mutagenesis in Cas9-edited founder mice. Sequencing and computational analysis indicate that the risk of Cas9 cutting at predicted off-target sites is lower than random genetic variation introduced into the genomes of inbred mice through mating. These findings will inform future design and use of Cas9-edited animal models and can provide context for evaluating off-target potential in genetically diverse patient populations. Supported by ORIP (UM1OD023221, UM1OD023222) and NHGRI.
The Landscape of Tolerated Genetic Variation in Humans and Primates
Gao et al., Science. 2023.
Investigators created a whole-genome sequence database from 809 nonhuman primates (NHPs) of 233 species to test the hypothesis that gene variants that do not cause disease in NHPs would likely be benign also in humans. They found that 99% of the genetic variants that were benign in NHPs also were classified as benign in the human ClinVar database. In contrast, only 71% to 87% of genomic variants classified as benign in non-primate animals were benign in humans. Building on this approach, the authors reclassified more than 4 million human genetic variants of unknown health impact as likely being benign based on effects in NHPs. This work illustrates the power of comparative medicine approaches between NHPs and humans. Supported by ORIP (P40OD024628, P51OD011106) and NIGMS.
A Global Catalog of Whole-Genome Diversity from 233 Primate Species
Kuderna et al., Science. 2023.
https://pubmed.ncbi.nlm.nih.gov/37262161/
Researchers are interested in studying the remarkable diversity of morphology and behavior across primates to answer long‑standing questions in evolutionary and conservation biology. Using whole-genome sequencing, the investigators created a nuclear DNA phylogeny and reassessed evolutionary divergence times among primate clades. They found that intraspecies genetic diversity across families and geographic regions was associated with climate and sociality, but not with extinction risk. Furthermore, mutation rates differed among species, potentially influenced by effective population sizes. Lastly, they identified extensive recurrence of missense mutations that previously were thought to be human specific. Supported by ORIP (P40OD024628).
p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
Faget et al., Cancer Discovery. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/
This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.