Biology subjects

Oakes, C.

Publications and source records attributed to Oakes, C..

4 recordsLinked to original sources

bioRxiv2026

LncRNA-mediated organization of oncogenic chromatin state is a targetable vulnerability in leukemia

Long non-coding RNAs (lncRNAs) are increasingly recognized as critical regulators of gene expression underlying various cellular functions, however, the functional and mechanistic contributions of most lncRNAs to tumorigenesis remain poorly defined, and targeting of lncRNAs is challenging with conventional therapeutic approaches. Here, we uncover human PAN3-AS1 and its murine ortholog Lnc35682, previously uncharacterized lncRNAs embedded within a conserved syntenic genomic locus, as highly expressed in acute myeloid leukemia (AML). Using genetic mouse models, human cell lines and primary patient samples, we show that PAN3-AS1 is essential for leukemia maintenance but dispensable for normal hematopoiesis. Mechanistically, we find that elevated PAN3-AS1 influences chromatin accessibility, thus promoting leukemia gene expression programs. This is mediated, at least in part, by PAN3-AS1s association with the nuclear lamina through a defined functional region that is required for its leukemogenic function. We further characterize a feed-forward regulatory circuit between PAN3-AS1 and its neighboring gene FLT3 that directly links the aberrant lncRNA functions to the FLT3-mutant AML subtype. To therapeutically exploit the regulatory node, we engineer a myeloid leukemia-preferentially targeted lipid nanoparticle (LNP) formulation and demonstrate effective delivery of siRNAs against endogenous targets into leukemia cells in experimental animals. LNP-siPAN3-AS1 alone or in combination with a clinically used FLT3 inhibitor, Gilteritinib, reduces leukemia burden and significantly delay leukemogenesis in vivo. Overall, our study uncovers a therapeutic vulnerable lncRNA-centric circuitry and provides compelling preclinical evidence for the development and application of a novel RNA targeting-LNP based therapy for treatment of myeloid leukemia. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/744058v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@10c9d42org.highwire.dtl.DTLVardef@12864e7org.highwire.dtl.DTLVardef@f87f6aorg.highwire.dtl.DTLVardef@750cbf_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Microvascular architecture and dynamics of the choroid plexus brain barrier

The choroid plexus is a specialized blood-cerebrospinal fluid barrier that supports cerebrospinal fluid production, immune surveillance, and molecular exchange between the circulation and the central nervous system, yet its vascular bed remains poorly understood. Here, we combine whole-tissue clearing and light-sheet imaging, single-nucleus transcriptomic reanalysis, and live calcium imaging of intact murine explants to define the structural and functional organization of choroid plexus endothelial networks across development. Three-dimensional imaging and reconstruction highlights a dense, epithelial-ensheathed vascular plexus that is continuous with the broader cerebrovasculature and organized into anatomically distinct inflow and ventricular margin regions. Transcriptomic analysis identified developmentally stratified endothelial subtypes, with embryonic populations enriched for proliferative, motor, and membrane remodeling programs and adult and aged populations enriched for adhesion, extracellular matrix, transport, and mechanosensory pathways. Endothelial subsets across stages expressed genes linked to flow sensing and calcium-dependent mechanotransduction, including Piezo1, Piezo2, and Trpv4. Consistent with these signatures, intact explants exhibited spontaneous, spatially graded calcium oscillations, and pharmacologic activation by Piezo1, triggered robust network-wide calcium responses in embryonic and adult tissue with distinct temporal dynamics. Piezo1 activation also promoted stabilization of PECAM1-associated endothelial adhesion under ex vivo flow conditions. Together, these findings establish the choroid plexus endothelium as a structurally specialized, developmentally dynamic, and mechanosensitive vascular network and provide a framework for investigating endothelial contributions to blood-cerebrospinal fluid barrier function in health and disease.

neuroscience↗

bioRxiv2024

Long-read sequencing transcriptome quantification with lr-kallisto

RNA abundance quantification has become routine and affordable thanks to high-throughput "short-read" technologies that provide accurate molecule counts at the gene level. Similarly accurate and affordable quantification of definitive fulllength, transcript isoforms has remained a stubborn challenge, despite its obvious biological significance across a wide range of problems. "Long-read" sequencing platforms now produce data-types that can, in principle, drive routine definitive isoform quantification. However some particulars of contemporary long-read datatypes, together with isoform complexity and genetic variation, present bioinformatic challenges. We show here, using ONT data, that fast and accurate quantification of long-read data is possible and that it is improved by exome capture. To perform quantifications we developed lr-kallisto, which adapts the kallisto bulk and single-cell RNA-seq quantification methods for long-read technologies.

bioinformatics↗

bioRxiv2020

The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome

We report a systematic analysis of the biological and clinical implications of DNA methylation variability in five categories of B-cell tumors derived from B cells spanning the entire maturation spectrum. We used 2056 primary samples including training and validation series and show that 88% of the human DNA methylome is dynamically modulated under normal and neoplastic conditions. B-cell tumors display both epigenetic imprints of their cellular origin and de novo, disease-specific epigenetic alterations that in part are related to differential transcription factor binding. These differential methylation patterns were used by a machine-learning approach to create a diagnostic algorithm that accurately classifies 14 B-cell tumor entities and subtypes with different clinical management. Beyond this, we identified extensive patient-specific epigenetic variability targeting constitutively silenced chromatin regions, a phenomenon we could relate to the proliferative history of normal and neoplastic B cells. We observed that, depending on the maturation stage of the tumor cell of origin, mitotic activity leaves different imprints into the DNA methylome. Subsequently, we constructed a novel DNA methylation-based mitotic clock called epiCMIT (epigenetically-determined Cumulative MIToses), whose lapse magnitude represents a strong independent prognostic variable within specific B-cell tumor subtypes and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracker of B-cell tumor developmental history, with implications in the differential diagnosis and prediction of the outcome of the patients.

cancer biology↗