Biology subjects

Park, S. R.

Publications and source records attributed to Park, S. R..

3 recordsLinked to original sources

bioRxiv2025

Autism-associated ASPM variant causes macrocephaly and social-cognitive deficits in mice

In autism spectrum disorder (ASD), a neurodevelopmental disorder with social-cognitive deficits, macrocephaly occurs in 20% of patients with severe symptoms. However, the role of macrocephaly in ASD pathogenesis remains unclear. Here, we address the mechanistic link between macrocephaly and ASD by investigating a novel ASD-associated gain-of-function A1877T mutation in ASPM (abnormal spindle-like microcephaly-associated). ASPM is a key regulator of cortical size and cell proliferation expressed in both excitatory and inhibitory neuronal progenitors but not in differentiated neurons. We found that Aspm gain-of-function knock-in mice exhibit macrocephaly, excessive embryonic neurogenesis with expanded outer radial glia, an increased excitatory-inhibitory (E-I) ratio, brain hyperconnectivity, and social-cognitive deficits with male specificity. Our results suggest that macrocephaly in ASD is not a proportional expansion of excitatory and inhibitory neurons, but a shift in the E-I ratio, independent of the expression patterns of the causative gene. Thus, macrocephaly alone can cause a subset of ASD-like symptoms.

neuroscience↗

bioRxiv2021

A new method for improving extraction efficiency and purity of urine and plasma cell-free DNA

This study assessed three commercially available cell-free DNA (cfDNA) extraction kits and the impact of a PEG-based DNA cleanup procedure (DNApure) on cfDNA quality and yield. Six normal donor urine and plasma samples, and specimens from four pregnant (PG) women carrying male fetuses underwent extractions with the JBS cfDNA extraction kit (kit J), MagMAX Cell-Free DNA Extraction kit (kit M), and QIAamp Circulating Nucleic Acid Kit (kit Q). Recovery of a PCR product spike-in, endogenous TP53, and Y-chromosome DNA was used to assess kit performance. Nucleosomal-sized DNA profiles varied among the kits, with prominent multi-nucleosomal-sized peaks present in urine and plasma DNA isolated by kits J and M only. Kit J recovered significantly more spike-in DNA compared with kit M or Q (p<0.001) from urine, and similar amounts from plasma (p=0.12). Applying DNApure to kit M- and Q-isolated DNA significantly improved the amplification efficiency of spike-in DNA from urine (p<0.001) and plasma (p[≤]0.013). Furthermore, kit J isolated significantly more Y-chromosome DNA from PG urine compared to kit Q (p=0.05). We conclude that DNApure provides an efficient means of improving the yield and purity of cfDNA and minimizing effects of pre-analytical biospecimen variability on liquid biopsy assay performance.

molecular biology↗

bioRxiv2019

Heterogeneous transcriptome response to DNA damage at single cell resolution.

Cancer cells often heterogeneously respond to genotoxic chemotherapy, leading to fractional killing and chemoresistance1, 2, which remain as the major obstacles in cancer treatment. It is widely believed that DNA damage induces a uniform response in regulating transcription and that cell fate is passively determined by a threshold mechanism evaluating the level of transcriptional responses3. On the contrary to this assumption, here we show that a surprisingly high level of heterogeneity exists in individual cell transcriptome responses to DNA damage, and that these transcriptome variations dictate the cell fate after DNA damage. Many DNA damage response genes, including tumor suppressor p53 targets, were exclusively expressed in only a subset of cells having specific cell fate, producing unique stress responses tailored for the fate that the cells are committed to. For instance, CDKN1A, the best known p53 target inhibiting cell cycle, was specifically expressed in a subset of cells undergoing cell cycle checkpoint, while other pro-apoptotic p53 targets were expressed only in cells undergoing apoptosis. A small group of cells exhibited neither checkpoint nor apoptotic responses, but produced a unique transcriptional program that conferred strong chemoresistance to the cells. The heterogeneous transcriptome response to DNA damage was also observed at the protein level in flow cytometry. Our results demonstrate that cell fate heterogeneity after DNA damage is mediated by distinct transcriptional programs generating fate-specific gene expression landscapes. This finding provides an important insight into understanding heterogeneous chemotherapy responses of cancer cells.

cell biology↗