RESUMEN
Elucidating the cellular organization of the cerebral cortex is critical for understanding brain structure and function. Using large-scale single-nucleus RNA sequencing and spatial transcriptomic analysis of 143 macaque cortical regions, we obtained a comprehensive atlas of 264 transcriptome-defined cortical cell types and mapped their spatial distribution across the entire cortex. We characterized the cortical layer and region preferences of glutamatergic, GABAergic, and non-neuronal cell types, as well as regional differences in cell-type composition and neighborhood complexity. Notably, we discovered a relationship between the regional distribution of various cell types and the region's hierarchical level in the visual and somatosensory systems. Cross-species comparison of transcriptomic data from human, macaque, and mouse cortices further revealed primate-specific cell types that are enriched in layer 4, with their marker genes expressed in a region-dependent manner. Our data provide a cellular and molecular basis for understanding the evolution, development, aging, and pathogenesis of the primate brain.
Asunto(s)
Corteza Cerebral , Macaca , Análisis de la Célula Individual , Transcriptoma , Animales , Humanos , Ratones , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Macaca/metabolismo , Transcriptoma/genéticaRESUMEN
The European rabbit (Oryctolagus cuniculus) is important as a biomedical model given its unique features in immunity and metabolism. The current reference genome OryCun2.0 established with whole-genome shotgun sequencing was quite fragmented and had not been updated for ten years. In this work, we provided a new rabbit genome assembly UM_NZW_1.0 to improve OryCun2.0 by leveraging the contig lengths based on long-read sequencing and a wealth of available Illumina paired-end sequence data. UM_NZW_1.0 showed a remarkable increase of continuity compared with OryCun2.0, with 5 times longer contig N50 and approximately 75% gaps closed. Many of the closed gaps were overlapped with protein-coding genes or transcriptional features, resulting in an enhancement of gene annotations. In particular, UM_NZW_1.0 presented a more complete landscape of the MHC region and the IGH locus, therefore provided a valuable resource for future researches on rabbits.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Animales , Anotación de Secuencia Molecular , Conejos , Análisis de Secuencia de ADN , Secuenciación Completa del GenomaRESUMEN
Ependymoma is the third most common pediatric tumor with posterior fossa group A (PFA) being its most aggressive subtype. Ependymomas are generally refractory to chemotherapies and thus lack any effective treatment. Here, we report that elevated expression of CXorf67 (chromosome X open reading frame 67), which frequently occurs in PFA ependymomas, suppresses homologous recombination (HR)-mediated DNA repair. Mechanistically, CXorf67 interacts with PALB2 and inhibits PALB2-BRCA2 interaction, thereby inhibiting HR repair. Concordantly, tumor cells with high CXorf67 expression levels show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with radiotherapy. Thus, our findings have revealed a role of CXorf67 in HR repair and suggest that combination of PARP inhibitors with radiotherapy could be an effective treatment option for PFA ependymomas.
Asunto(s)
Proteína BRCA2/metabolismo , Ependimoma/terapia , Proteína del Grupo de Complementación N de la Anemia de Fanconi/metabolismo , Neoplasias Infratentoriales/terapia , Proteínas Oncogénicas/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Quimioradioterapia , Ependimoma/genética , Ependimoma/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Humanos , Neoplasias Infratentoriales/genética , Neoplasias Infratentoriales/metabolismo , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Oncogénicas/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Reparación del ADN por Recombinación/efectos de los fármacos , Reparación del ADN por Recombinación/efectos de la radiación , Regulación hacia Arriba , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Breast cancer is a heterogeneous disease. In particular, triple-negative breast cancer (TNBC) comprises various molecular subgroups with unclear identities and currently has few targeted treatment options. Our previous study identified protein C receptor (Procr) as a surface marker on mammary stem cells (MaSCs) located in the basal layer of the normal mammary gland. Given the possible connection of TNBC with basal layer stem cells, we conducted comparative analyses of Procr in breast cancers of mouse and human origin. In mouse mammary tumors, we showed that Procr+ cells are enriched for cancer stem cells (CSCs) in Wnt1 basal-like tumors, but not in Brca1 basal-like tumors or PyVT luminal tumors. In human cancers, PROCR was robustly expressed in half of TNBC cases. Experiments with patient-derived xenografts (PDXs) revealed that PROCR marks CSCs in this discrete subgroup (referred to as PROCR+ TNBC). Interfering with the function of PROCR using an inhibitory nanobody reduced the CSC numbers, arrested tumor growth and prevented rapid tumor recurrence. Our data suggest a key role of MaSC in breast tumorigenesis. Moreover, our work indicates that PROCR can be used as a biomarker to stratify TNBC into clinically relevant subgroups and may provide a novel targeted treatment strategy for this clinically important tumor subtype.