Biology subjects

Atlasi, Y.

Publications and source records attributed to Atlasi, Y..

3 recordsLinked to original sources

bioRxiv2024

Hao-Fountain syndrome protein USP7 controls neuronal differentiation via BCOR-ncPRC1.1

Pathogenic variants in the ubiquitin-specific protease 7 (USP7) gene cause a neurodevelopmental disorder called Hao-Fountain syndrome. However, which of USP7s pleiotropic functions are relevant for neurodevelopment remains unclear. Here, we present a combination of quantitative proteomics, transcriptomics and epigenomics to define the USP7 regulatory circuitry during neuronal differentiation. USP7 activity is required for the transcriptional programs that direct both differentiation of embryonic stem cells into neural stem cells, and the neuronal differentiation of SH-SY5Y neuroblastoma cells. USP7 controls the dosage of the Polycomb H2AK119ub1 ubiquitin ligase complexes ncPRC1.1 and ncPRC1.6. Loss-of-function experiments revealed that BCOR-ncPRC1.1, but not ncPRC1.6, is a key effector of USP7 during neuronal differentiation. Indeed, BCOR-ncPRC1.1 mediates a major portion of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neurodifferentiation, our results suggest that USP7 and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.

molecular biology↗

bioRxiv2024

Translational control in the spinal cord regulates gene expression and pain hypersensitivity in the chronic phase of neuropathic pain

Sensitization of spinal nociceptive circuits plays a crucial role in neuropathic pain. This sensitization depends on new gene expression that is primarily regulated via transcriptional and translational control mechanisms. The relative roles of these mechanisms in regulating gene expression in the clinically relevant chronic phase of neuropathic pain are not well understood. Here, we show that changes in gene expression in the spinal cord during the chronic phase of neuropathic pain are substantially regulated at the translational level. Downregulating spinal translation at the chronic phase alleviated pain hypersensitivity. Cell-type-specific profiling revealed that spinal inhibitory and excitatory neurons exhibited substantial changes in translation after peripheral nerve injury. Notably, increasing translation selectively in all inhibitory neurons or parvalbumin-positive (PV+) interneurons, but not excitatory neurons, promoted mechanical pain hypersensitivity. Furthermore, increasing translation in PV+ neurons decreased their intrinsic excitability and spiking activity. Conversely, reducing translation in spinal PV neurons prevented the nerve injury-induced decrease in excitability but did not alleviate mechanical hypersensitivity. Together, these findings advance our understanding of translational control mechanisms in the spinal cord during neuropathic pain and highlight their cell-type- and phase-specific contributions to gene expression and pain hypersensitivity.

neuroscience↗

bioRxiv2023

Aberrant Wnt activation in recurrent genetically variant human pluripotent stem cells impairs cardiomyocyte differentiation and phenotype

Human pluripotent stem cell (hPSC)-derived cardiomyocytes have emerged as powerful tools for disease modelling and cell therapy. The production of cardiomyocytes from hPSCs typically requires expanding large numbers of hPSCs and maintaining them in culture for extended periods of time. This in turn predisposes hPSCs to the acquisition of non-random genetic changes, including recurrent gains of chromosome 1q. Here, we show that gain of chromosome 1q in hPSCs affects both the efficiency of differentiation to cardiomyocytes and phenotype of the differentiated cells. Mechanistically, we show that aberrant activation of the Wnt signalling pathway underpins the skewed differentiation of variant 1q hPSCs. Collectively, our data demonstrates that the presence of genetically variant cells in cultures is a significant concern for production of hPSC-derived cardiomyocytes for research or clinical applications. Further, our results suggest new approaches for removing genetically variant cells for future clinical applications.

cell biology↗