Biology subjects

Atamian, A.

Publications and source records attributed to Atamian, A..

2 recordsLinked to original sources

bioRxiv2026

Developmental determinants of male bias in medulloblastoma

Boys experience an overall increased incidence of several childhood cancers, including medulloblastoma, a clinically heterogeneous cerebellar tumor. In subtypes of Group 3 and Group 4 medulloblastoma, males are three times more prevalent than females. As medulloblastoma is suspected to initiate during fetal development, we hypothesized that this sex bias reflects a combination of prenatal, sex-specific developmental processes and somatic alterations. To test these hypotheses, we compiled a large multi-omics dataset from children with medulloblastoma, which revealed sex-specific alterations, including frequent loss of the inactive X chromosome in females with Group 4. Generation of a sex-matched single-cell transcriptome atlas of the developing murine cerebellum enabled investigation of putative developmental factors underlying sex bias. Progenitors giving rise to Group 3/4 subgroups were more abundant, more proliferative, and harbored more open chromatin for recruitment of LMX1A and OTX2, master transcription factors defining Group 3/4 identity. Advanced genetically engineered mouse models and human cerebellar organoids were leveraged to determine whether sexual dimorphism arises from intrinsic or extrinsic factors. These models showed that the XY genotype contributed to the phenotype, but the predominant effect was driven by presence of the male gonadal hormone testosterone. Our findings provide a sex-specific genetic and neurodevelopmental explanation for male bias in an aggressive pediatric brain tumor. Outcomes from this study may inform novel treatment strategies delivered according to sex and are likely to be broadly applicable to other sex-biased malignancies arising in early life. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/714163v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@566e41org.highwire.dtl.DTLVardef@607ae9org.highwire.dtl.DTLVardef@25679aorg.highwire.dtl.DTLVardef@1b4beec_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2023

An integrated transcriptomic cell atlas of human neural organoids

Neural tissues generated from human pluripotent stem cells in vitro (known as neural organoids) are becoming useful tools to study human brain development, evolution and disease. The characterization of neural organoids using single-cell genomic methods has revealed a large diversity of neural cell types with molecular signatures similar to those observed in primary human brain tissue. However, it is unclear which domains of the human nervous system are covered by existing protocols. It is also difficult to quantitatively assess variation between protocols and the specific cell states in organoids as compared to primary counterparts. Single-cell transcriptome data from primary tissue and neural organoids derived with guided or un-guided approaches and under diverse conditions combined with large-scale integrative analyses make it now possible to address these challenges. Recent advances in computational methodology enable the generation of integrated atlases across many data sets. Here, we integrated 36 single-cell transcriptomics data sets spanning 26 protocols into one integrated human neural organoid cell atlas (HNOCA) totaling over 1.7 million cells. We harmonize cell type annotations by incorporating reference data sets from the developing human brain. By mapping to the developing human brain reference, we reveal which primary cell states have been generated in vitro, and which are under-represented. We further compare transcriptomic profiles of neuronal populations in organoids to their counterparts in the developing human brain. To support rapid organoid phenotyping and quantitative assessment of new protocols, we provide a programmatic interface to browse the atlas and query new data sets, and showcase the power of the atlas to annotate new query data sets and evaluate new organoid protocols. Taken together, the HNOCA will be useful to assess the fidelity of organoids, characterize perturbed and diseased states and facilitate protocol development in the future.

developmental biology↗