Biology subjects

Chow, S.

Publications and source records attributed to Chow, S..

8 recordsLinked to original sources

bioRxiv2025

Aberrant splicing of MBD1 reshapes the epigenome to drive convergent myeloerythroid defects in MDS

Myelodysplastic neoplasms (MDS) feature hematopoietic deficits driven in part by transcript splicing abnormalities. Thus far, such disease-driving transcripts have been identified in association with specific splicing factor mutations. However, it remains unclear whether there also exists a set of disease-wide conserved pathological transcripts, which drive MDS independently of mutational status. Here, we characterize an MDS-associated long isoform of MBD1 (MBD1-L) as the first described member of this class of transcripts. Overexpression of MBD1-L in healthy human HSPCs recapitulates archetypal defects of MDS including deficits in erythroid differentiation and reconstitution capacity. These defects arise from an isoform-specific switching of MBD1s binding behavior, refocusing its heterochromatin-promoting activity from methylated to unmethylated CpGs and enacting broad downregulation of CpG-rich promoters as well as secondary epigenetic effects mediated by its downstream target BCOR. Remarkably, we also find that directly reversing abnormal MBD1 splicing in primary human MDS using nanoparticle-encapsulated ASOs enhances erythroid differentiation. Key pointsO_LIGlobal mis-splicing of MBD1 represents a novel gain-of-function epigenetic axis driving erythropoietic and proliferative defects in MDS. C_LIO_LIASO based depletion of pathogenic MBD1 transcripts restores erythroid differentiation, advancing RNA-based therapies for MDS. C_LI

cancer biology↗

bioRxiv2025

De novo heterozygous variants in EHMT2 genocopy Kleefstra syndrome via loss of G9a methyltransferase activity

EHMT1 and EHMT2 genes encode human euchromatin histone lysine methyltransferase 1 and 2 (EHMT1 alias GLP; EHMT2 alias G9a) that form heteromeric GLP/G9a complexes with essential roles in epigenetic regulation of gene expression. While EHMT1 haploinsufficiency has been established as the cause of Kleefstra syndrome 1, the pathogenesis of G9a dysfunction in human disease remains largely unknown. We identified seven de novo EHMT2 variants in patients with clinical presentation, episignatures, histone modifications and transcriptomic profiles similar to those of Kleefstra syndrome 1. In vitro studies revealed that these variants encode for structurally stable G9a proteins that are catalytically incompetent due to aberrant interactions either with histone H3 tail or with S-adenosylmethionine. Heterozygous mice carrying a patient-derived variant exhibited growth retardation, facial/skull dysmorphia and aberrant behavior. Here we report pathogenic EHMT2 variants that likely exert dominant-negative effect on GLP/G9a complexes and thus genocopy the EHMT1 haploinsufficiency via a distinct molecular mechanism, defining an autosomal dominant EHMT2-related Kleefstra syndrome.

genetics↗

bioRxiv2025

Detection of prostate cancer in 3D pathology datasets via generative immunolabeling

Recent advancements in nondestructive 3D pathology offer a complement to standard histology by enabling comprehensive volumetric analyses of intact clinical specimens (e.g. biopsies). Prior studies have demonstrated the added prognostic value of 3D pathology for prostate cancer risk stratification by correlating 3D microarchitectural features with long-term patient outcomes. However, these analyses relied on coarse manual annotations of cancer-enriched regions for downstream analysis without fine-grained delineation between often-intermixed cancerous and benign glands. To address these limitations, we have developed a 3D computational pipeline: Synthetic Immunolabeling for Generative Heatmaps of Tumor (SIGHT). SIGHT relies on deep learning-based 3D image translation models, trained in a fully supervised fashion, to convert H&E-analog 3D pathology datasets into multiplexed 3D immunofluorescence datasets that facilitate tumor detection. Our implementation of SIGHT synthetically labels two cytokeratin markers that are differentially expressed in cancerous and benign prostate glands, which are used to generate explainable 3D heatmaps of cancer-enriched regions in prostate tissues. Validation of SIGHT against ground-truth annotations from a panel of genitourinary pathologists yields an average F1 score of 0.88 which is comparable to the average inter-pathologist agreement F1 score of 0.90. To demonstrate the value of SIGHT, we developed machine classifiers of recurrence risk based on 3D glandular histomorphometric features from 75 patients. Volumetric glandular analysis in SIGHT-identified cancer-enriched regions vs. all tissue regions yields an average Kaplan-Meier hazard ratio of 3.57 (1.6 - 7.9 CI) vs. 0.92 (0.45 - 1.89 CI).

pathology↗

bioRxiv2022

Visualization of Incrementally Learned Projection Trajectories for Longitudinal Data

Longitudinal studies that continuously generate data enable the capture of temporal variations in experimentally observed parameters, facilitating the interpretation of results in a time-aware manner. We propose IL-VIS (Incrementally Learned Visualizer), a new machine learning pipeline that incrementally learns and visualizes a progression trajectory representing the longitudinal changes in longitudinal studies. At each sampling time point in an experiment, IL-VIS generates a snapshot of the longitudinal process on the data observed thus far, a new feature that is beyond the reach of classical static models. We first verify the utility and correctness of IL-VIS using simulated data, for which the true progression trajectories are known. We find that it accurately captures and visualizes the trends and (dis)similarities between high-dimensional progression trajectories. We then apply IL-VIS to longitudinal Multi-Electrode Array data from brain cortical organoids when exposed to different levels of Quinolinic Acid, a metabolite contributing to many neuroinflammatory diseases including Alzheimers disease, and its blocking antibody. We uncover valuable insights into the organoids electrophysiological maturation and response patterns over time under these conditions.

bioinformatics↗

bioRxiv2022

Variation of length and sequence of the nuclear ribosomal DNA internal transcribed spacer 1 supports hermit-to-king crab hypothesis

Lithodoid and paguroid crabs are morphologically assigned to the superfamilies Lithodoidea and Paguroidea, respectively. Molecular analyses, however, have revealed closer genetic proximity of the lithodoid crabs to the family Paguridae than to other families of Paguroidea, provoking a long debate. We investigated the length and nucleotide sequence variation of the nuclear ribosomal DNA internal transcribed spacer 1 (ITS1) in lithodoid and paguroid species. Uniquely short ITS1s (215-253 bp) were observed in seven lithodoid species belonging to the families Lithodidae and Hapalogastridae. In contrast, ITS1 length varied considerably in 13 paguroid species belonging to the families Coenobitidae, Diogenidae, and Paguridae. Short-to-long ITS1s (238-1090 bp) were observed in five species of the family Paguridae, and medium to long ITS1s (573-1166 bp) were observed in eight species of the families Coenobitidae and Diogenidae. Interestingly, ITS1s of considerably different sizes coexist in individual paguroid species. Nucleotide sequence analysis indicated that the short ITS1s observed in the family Paguridae were descendants of longer ITS1s and were homologous to the short ITS1 of lithodoid species. ITS1 sequences of the families Coenobitidae and Diogenidae shared no nucleotide elements similar to those of lithodoid and pagurid species. These molecular signals indicate that the short ITS1 in pagurid lineage was passed on to lithodoid lineage, strongly supporting the "hermit-to-king" crab hypothesis.

evolutionary biology↗

bioRxiv2019

FLASH irradiation enhances the therapeutic index of abdominal radiotherapy in mice

Peritoneal metastases are the leading cause of morbidity and mortality in ovarian cancer. Despite current surgery, chemotherapy and targeted therapies, the majority of patients diagnosed with advanced epithelial ovarian cancer develop recurrent disease and overall survival rates remain poor. It is known that ovarian cancer is a radiosensitive tumor. Historically, total abdominal irradiation (TAI) was used as an effective postsurgical adjuvant therapy in the management of chemotherapy sensitive and resistant ovarian cancer. However, TAI fell out of favor due to high toxicity, particularly of the gastrointestinal tract. We have developed a preclinical irradiation platform that allows for total abdominal ultrahigh dose rate FLASH irradiation. We demonstrate that TAI-FLASH reduces radiation-induced intestinal injury in both healthy and tumor-bearing mice compared to conventional dose rate (CONV) irradiation. Single high dose TAI-FLASH reduced mortality from gastrointestinal syndrome, spared gut function and epithelial integrity, and decreased cell death in crypt base columnar cells. Importantly, FLASH and CONV irradiation had similar efficacy in the reduction of ovarian cancer peritoneal metastases. These findings suggest that FLASH irradiation may be an effective strategy to enhance the therapeutic index of radiotherapy for the treatment of metastatic ovarian cancer in women.

cancer biology↗

bioRxiv2019

Morphological differences between phyllosoma larvae from the midwestern and eastern Pacific populations of the pronghorn spiny lobster Panulirus penicillatus

The pronghorn spiny lobster Panulirus penicillatus is known to have the widest distribution among palinurid lobster species, occurring in tropical and sub-tropical areas of the Indo-Pacific Ocean. In the Pacific Ocean, mitochondrial DNA analyses have revealed that the western-central and eastern populations are genetically isolated. We performed morphological investigations on mid- to late-stage phyllosoma larvae collected in these two areas. The larvae of the western-central population had a significantly narrower cephalic shield, shorter abdomen, and longer eyestalk than those of the eastern population. Additionally, for larvae larger than about 25-mm body length, the widest position of the cephalic shield in the western-central population was located closer to the middle of the median line of the cephalic shield than that in the eastern population. The ratio of width to length of cephalic shield and the ratio of cephalic shield width to thorax width are key traits for distinguishing between the larvae of the two populations.

ecology↗

bioRxiv2018

Islet macrophages are the primary islet source of IGF-1 and improve glucose homeostasis following pancreatic beta-cell death.

Macrophages play a dynamic role in tissue repair following injury. Here we found that following streptozotocin (STZ)-induced beta-cell death, mouse islet macrophages expressed increased Igf1, decreased proinflammatory cytokine expression, and transcriptome changes consistent with macrophages undergoing efferocytosis and having an enhanced state of metabolism. Macrophages were the major, if not sole, contributors to islet IGF-1 production. Adoptive transfer experiments showed that macrophages can maintain insulin secretion in vivo following beta-cell death with no effects on islet-cell turnover. IGF-1 neutralization during STZ-treatment decreased insulin secretion without affecting islet-cell apoptosis or proliferation. Interestingly, high fat diet (HFD) combined with STZ further skewed islet macrophages to a reparative state. Finally, islet macrophages from db/db mice also expressed decreased proinflammatory cytokines and increased Igf1 mRNA. These data have important implications for islet biology and pathology and show that islet macrophages preserve their reparative state following beta-cell death even during HFD feeding and severe hyperglycemia.

immunology↗