Biology subjects

Siantoputri, M. E.

Publications and source records attributed to Siantoputri, M. E..

3 recordsLinked to original sources

bioRxiv2026

GPCRs as Targets for Human Brain Modulation: A Multi-omic Atlas of Cell-Type Specific Expression

G Protein coupled receptors (GPCRs) are the largest class of clinically validated drug targets with nearly 35% of all approved therapeutic agents acting on these receptors. To further explore the potential of this class of receptors for the development of circuit-specific and mechanism-based therapeutic strategies for neurological disorders, we focused on GPCRs with no known endogenous ligand, orphan GPCRs (oGPCRs), because knowledge of their functions in the human brain remains rudimentary. Here, we utilized fluorescence activated nuclear sorting and sequencing (FANSseq) to generate deep molecular profiles of cell type specific nuclei isolated from post-mortem brains to generate an atlas of oGPCR expression across multiple regions of the human brain. We identified 22 oGPCRs that displayed selective cell-type enrichment both in RNA transcript expression and chromatin accessibility. We further validated each of these targets for cell-type specific expression in human brains and developed an open-source web atlas of all oGPCR expression in the human brain to serve as a neuro-resource for the broader scientific community. These studies reveal novel cell-type specific expression patterns of several oGPCRs, suggest potential endogenous roles for these receptors, and identify validated candidates for cell-type specific neuromodulation of the human brain. One Sentence SummaryThis study presents an atlas of orphan GPCR expression across the human brain for translational targeting.

neuroscience↗

bioRxiv2025

Epigenetic mechanisms governing cell type specific somatic expansion and toxicity in Huntington's disease

Huntingtons disease (HD) is characterized by neuronal dysfunction and degeneration that varies markedly by brain region and cell type. Using high-resolution epigenetic profiling of postmortem human cell types we identify a pathogenic cascade linking cell type specific enhancer activity to somatic CAG expansion, and toxicity to epigenetic dysregulation. Enhancers regulating mismatch-repair (MMR) gene expression explain the specificity of expansion. In the second, toxic phase of HD we identify two distinct epigenetic mechanisms that disrupt regulation of hundreds of genes in the majority of HD MSNs, including several that cause haploinsufficient neurological disorders. Together, these data unify enhancer function, impaired DNA demethylation, and transcriptional dysregulation into a single model highlighting therapeutic opportunities that combine inhibition of somatic CAG expansion with restoration of neuronal DNA demethylation.

neuroscience↗

bioRxiv2025

Open-source Photobleacher for Fluorescent Imaging of Large Pigment-Rich Tissues

Fluorescent imaging enables visualization of the specific molecules of interest with high contrast, and the use of multiple fluorophores in a single tissue sample allows visualization of complex relationships between biological molecules, cell types, and anatomy. The utility of fluorescent imaging in human tissue has been limited by endogenous pigments that can block the light path or emit an autofluorescence, thereby interfering with the specific imaging of target molecules. Although photobleachers have been developed to quench endogenous pigments, the lack of customizability limits their utility for a broad range of applications. Here, we present a high luminous-intensity photobleacher that is based on rigorous simulations of illumination patterns using the laws of radiation, along with the framework to maximize bleaching efficiency. This open-source project is designed to help researchers customize and scale according to the tissue types and the research goals. The photobleacher is applicable to both thin tissue slices and large-volume cleared tissue samples to enable serial three-dimensional imaging of postmortem human brain using multiplexed antibody or oligonucleotide probes. SIGNIFICANCE STATEMENTPhotobleaching is an effective technique for quenching endogenous pigments, enabling multiplexed fluorescent imaging of pigment-rich tissues, such as postmortem human samples. While many photobleaching strategies have been proposed, there is no standard guidance on how to design and use a photobleacher. This study introduces a general strategy for designing an effective, scalable, and customizable photobleacher, and proposes a workflow for properly treating tissues with the photobleacher. The technique enables high-contrast molecular visualization in tissues of various sizes, including large volumetric cleared tissues. Our framework will accelerate the quantitative understanding of human molecular anatomy and is applicable to diverse biological fields, including medical diagnostics.

neuroscience↗