Selected Grantee Publications
Topologically Associating Domain Boundaries Are Required for Normal Genome Function
Rajderkar et al., Communications Biology. 2023.
https://www.nature.com/articles/s42003-023-04819-w
Eukaryotic genomes fold into topologically associating domains (TADs), sub-megabase-scale chromatin segments characterized by high intra-domain chromatin contact frequency. Investigators selected eight independent TAD boundaries in the vicinity of genes active during embryonic development, individually deleted these boundaries from the mouse genome, and systematically examined the consequences on survival, genome organization, gene expression, and development. Results of the studies demonstrate the importance of TAD boundary sequences for in vivo genome function and reinforce the critical need to consider the potential pathogenicity of deletions affecting TAD boundaries in clinical genetics screening. Supported by ORIP (UM1OD023221), NIGMS, and NHGRI.
Identification of a Heterogeneous and Dynamic Ciliome during Embryonic Development and Cell Differentiation
Elliott et al., Development. 2023.
Ciliopathies are a class of diseases that arise when the structure or function of the cilium is compromised. To definitively determine the extent of heterogeneity within the ciliome, investigators compared the ciliomes of six distinct embryonic domains. The data comprehensively revealed that about 30% of the ciliome is differentially expressed across analyzed tissues in the developing embryo. Furthermore, upregulation of numerous ciliary genes correlated with osteogenic cell-fate decisions, suggesting that changes in the ciliome contribute to distinct functions of cell types in vertebrate species. Supported by ORIP (UM1OD023222), NIDCR, and NIGMS.
Pembrolizumab and Cabozantinib in Recurrent Metastatic Head and Neck Squamous Cell Carcinoma: A Phase 2 Trial
Saba et al., Nature Medicine. 2023.
https://www.doi.org/10.1038/s41591-023-02275-x
A multicenter clinical trial was conducted in 33 evaluable (36 enrolled) patients with recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC) on a regimen combining cabozantinib, a tyrosine kinase inhibitor, with the standard of care of anti–programmed cell death protein 1 agent pembrolizumab. Results showed that 17 patients (52%) exhibited partial response and 13 (39%) exhibited stable disease, with an overall clinical benefit rate of 91%. Median progression-free survival (PFS) was 14.6 months, and the 1-year PFS was 54%. The pembrolizumab and cabozantinib regimen was well tolerated in patients with RMHNSCC. The promising clinical benefit warrants further investigation. Supported by ORIP (S10OD021644), NCI, and NIDCR.
Production and Characterization of Monoclonal Antibodies to Xenopus Proteins
Horr et al., Development. 2023.
https://pubmed.ncbi.nlm.nih.gov/36789951/
Monoclonal antibodies are powerful and versatile tools that enable the study of proteins in diverse contexts. They are often utilized to assist with identification of subcellular localization and characterization of the function of target proteins of interest. However, because there can be considerable sequence diversity between orthologous proteins in Xenopus and mammals, antibodies produced against mouse or human proteins often do not recognize Xenopus counterparts. To address this issue, the authors refined existing mouse monoclonal antibody production protocols to generate antibodies against Xenopus proteins of interest. Here, they describe several approaches for the generation of useful mouse anti-Xenopus antibodies to multiple Xenopus proteins and their validation in various experimental approaches. Supported by ORIP (R24OD021485, S10OD010645) and NIDCR.
TMEM161B Modulates Radial Glial Scaffolding in Neocortical Development
Wang et al., PNAS. 2023.
https://www.pnas.org/doi/10.1073/pnas.2209983120
Neocortical folding (i.e., gyrification) is a fundamental evolutionary mechanism allowing the expansion of cortical surface area and increased cognitive function. This study identifies TMEM161B in gyral spacing in humans, likely affecting radial glial cell polarity through effects on the actin cytoskeleton. Patients carrying TMEM161B mutations exhibit striking neocortical polymicrogyria and intellectual disability. TMEM161B knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. The data implicating TMEM161B in murine holoprosencephaly may suggest shared mechanisms between the formation of the brain midline and cortical gyrification. Supported by ORIP (U54OD030187), NINDS, and NHGRI.
Two Neuronal Peptides Encoded from a Single Transcript Regulate Mitochondrial Complex III in Drosophila
Bosch et al., eLife. 2022.
https://www.doi.org/10.7554/eLife.82709
Transcripts with small open-reading frames (smORFs) are underrepresented in genome annotations. Functions of peptides encoded by smORFs are poorly understood. The investigators systematically characterized human-conserved smORF genes in Drosophila and found two peptides, Sloth1 and Sloth2, that are highly expressed in neurons. They showed that Sloth1 and Sloth2 are paralogs with high sequence similarity but are not functionally redundant. Loss of either peptide resulted in lethality, impaired mitochondrial function, and neurodegeneration. This work suggests the value of phenotypic analysis of smORFs using Drosophila as a model. Supported by ORIP (R24OD019847), NHGRI, and NIGMS.
Mendelian Gene Identification through Mouse Embryo Viability Screening
Cacheiro et al., Genome Medicine. 2022.
https://www.doi.org/10.1186/s13073-022-01118-7
The investigators dissected phenotypic similarities between patients and model organisms by assessing the embryonic stage at which homozygous loss of function results in lethality in mice of both sexes obtained from the International Mouse Phenotyping Consortium. Information on knockout mouse embryo lethality can be used to prioritize candidate genes associated with certain disorders. Access to unsolved cases from rare-disease genome sequencing programs allows for the screening of those genes for potentially pathogenic variants, which could lead to a diagnosis and new potential treatment options to inform the management of human disease. Supported by ORIP (UM1OD023221, UM1OD023222, U42OD011174) and NHGRI.
Promoting Validation and Cross-Phylogenetic Integration in Model Organism Research
Cheng et al., Disease Models & Mechanisms. 2022.
https://www.doi.org/10.1242/dmm.049600
Model organisms are essential for biomedical research and therapeutic development, but translation of such research to the clinic is low. The authors summarized discussions from an NIH virtual workshop series, titled “Validation of Animal Models and Tools for Biomedical Research,” held from 2020 to 2021. They described challenges and opportunities for developing and integrating tools and resources and provided suggestions for improving the rigor, validation, reproducibility, and translatability of model organism research. Supported by ORIP (R01OD011116, R24OD031447, R03OD030597, R24OD018559, R24OD017870, R24OD026591, R24OD022005, U42OD026645, U42OD012210, U54OD030165, UM1OD023221, P51OD011107), NIAMS, NIDDK, NIGMS, NHGRI, and NINDS.
Molecular and Cellular Evolution of the Primate Dorsolateral Prefrontal Cortex
Ma et al., Science. 2022.
https://www.doi.org/10.1126/science.abo7257
The dorsolateral prefrontal cortex (dlPFC) exists only in primates, lies at the center of high-order cognition, and is a locus of pathology underlying many neuropsychiatric diseases. The investigators generated single-nucleus transcriptome data profiling more than 600,000 nuclei from the dlPFC of adult humans, chimpanzees, rhesus macaques, and common marmosets of both sexes. Postmortem human samples were obtained from tissue donors. The investigators’ analyses delineated dlPFC cell-type homology and transcriptomic conservation across species and identified species divergence at the molecular and cellular levels, as well as potential epigenomic mechanisms underlying these differences. Expression patterns of more than 900 genes associated with brain disorders revealed a variety of conserved, divergent, and group-specific patterns. The resulting data resource will help to vertically integrate marmoset and macaque models with human-focused efforts to develop treatments for neuropsychiatric conditions. Supported by ORIP (P51OD011133), NIA, NICHD, NIDA, NIGMS, NHGRI, NIMH, and NINDS.
Early Treatment Regimens Achieve Sustained Virologic Remission in Infant Macaques Infected with SIV at Birth
Wang et al., Nature Communications. 2022.
https://www.doi.org/10.1038/s41467-022-32554-z
About 150,000 children are infected postnatally with HIV each year. Early antiretroviral therapy (ART) in infants with HIV can reduce viral reservoir size, but ART-free virologic remission has not been achieved. The researchers hypothesized that proviral reservoir seeding in infants exposed to HIV might differ from that in adults. They characterized viral reservoirs in neonatal rhesus macaques of both sexes inoculated with simian immunodeficiency virus (SIV) at birth and given combination ART. The researchers reported that 9 months of treatment initiated at day 3 resulted in a sustained virologic remission, suggesting that early intervention with proper treatment regimens could be an effective strategy. Supported by ORIP (P51OD011104), NIAID, NICHD, and NIDCR.