Biology subjects

Moran, S. P.

Publications and source records attributed to Moran, S. P..

8 recordsLinked to original sources

bioRxiv2026

Reference-Guided De Novo Retrieval of 3D Chromatin Organizational Features with Representation Learning

Chromosome conformation maps reveal spatial genome organization through recurring contact patterns, some associated with established architectural features and others with less understood biological processes. Identifying instances of a pattern across these maps is necessary to investigate its biological associations and recurrence across experimental settings. However, conventional feature callers typically target predefined patterns, offering limited support when researchers can provide examples of a feature of interest but lack a dedicated detection method. We introduce Chromatin Fetch (C-Fetch), a reference-guided retrieval framework that uses examples of a desired feature and a contrasting class to rank and assign contact-map patches at provided candidate coordinates. C-Fetch learns a reusable representation through weakly KL-regularized 3D autoencoding of structurally related, non-temporal Hi-C and Micro-C patches without architectural feature labels. We demonstrate retrieval of biologically defined contacts, visually specified patterns, and established architectural features. Polycomb-guided retrieval identifies contacts enriched for PRC2-associated signals, exceeding enrichment from loop-guided assignments at 5 kb, while queries resembling condensed domains retrieve patches with progressively stronger rectangular enrichment at higher ranks. Loop-guided retrieval increases aggregate focal enrichment relative to complete Mustache proposal sets across four held-out maps, and selected contacts show greater focality loss after cohesin depletion than matched remaining candidates. Retrieval also extends to Region Capture Micro-C and HiChIP, with ranking agreement retained across biological replicates and reduced sequencing depths. Together, these results establish reference examples as a flexible means of specifying contact-map features of interest, enabling biological investigation, exploration of visual patterns, and refinement of existing calls across datasets and technologies.

bioinformatics↗

bioRxiv2026

Discovery of GluA3 preferring AMPA receptor positive allosteric modulator BRD3290

Schizophrenia is a debilitating neuropsychiatric disease that lacks effective treatments for many symptom domains including negative, cognitive and sleep disturbances. Lack of clear disease etiology has hampered the development of new, effective treatments for the unmet needs of people with schizophrenia. Large scale human genetics have identified rare loss of function mutations that substantially increase risk of developing schizophrenia, including in GRIA3, the gene that encodes the GluA3 receptor subunit of the AMPA receptor (AMPAR). Several drug discovery programs have been aimed at developing AMPAR positive allosteric modulators (PAMs) as a novel treatment for schizophrenia. Despite intense drug discovery efforts, there are no FDA approved AMPAR PAMs. We therefore hypothesized that selectively targeting GluA3, the AMPAR subunit implicated by human genetics, could yield a safer and more effective AMPAR PAM for the potential treatment of schizophrenia. Using a combination of medicinal chemistry, in vitro, and in vivo studies, we discovered BRD3290, a GluA3-preferring AMPAR PAM with reasonable potency in heterologous cells, as well as favorable tolerability and brain exposure. Peripheral administration of BRD3290 engaged an established AMPAR PAM target engagement biomarker but did not improve performance of wildtype mice in the novel object recognition task (NOR), in contrast to the nonselective AMPAR PAM PF-4778574, which improved mouse NOR. These findings suggest that the GluA3 selectivity profile of BRD3290 was insufficient to enhance cognitive function in this mouse NOR paradigm. This work highlights the challenges of AMPAR subtype-selective modulation and provides molecular insights into the ability to develop subtype-selective AMPAR PAMs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/740780v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1577f62org.highwire.dtl.DTLVardef@16c1750org.highwire.dtl.DTLVardef@16eaef3org.highwire.dtl.DTLVardef@19fdb6f_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

Screening the human druggable genome identifies ABHD17B as an anti-fibrotic target in hepatic stellate cells

Hepatic stellate cells (HSCs) are activated with chronic liver injury and transdifferentiate into myofibroblasts, which produce excessive extracellular matrices that form the fibrotic scar. While the progression of fibrosis is understood to be the cause of end-stage liver disease, there are no approved therapies directed at interfering with the activity of HSC myofibroblasts. We performed a high-throughput small interfering RNA (siRNA) screen in primary human HSC myofibroblasts to identify gene products necessary for the fibrotic phenotype of HSCs. We found that depletion of ABHD17B promotes the inactivation of HSCs, characterized by reduced COL1A1 and ACTA2 expression and accumulation of lipid droplets. Mice deficient for Abhd17b are also protected from fibrosis in the setting of in vivo liver injury. While ABHD17B is a depalmitoylase, our data suggest that ABHD17B promotes fibrosis through pathways independent of depalmitoylation that include interaction with MYO1B to modulate gene expression and HSC migration. Together, our results provide an analysis of the phenotypic consequences for siRNAs targeting RNAs from >9,500 genes in primary human HSCs and identify ABHD17B as a potential therapeutic target to inhibit liver fibrosis.

cell biology↗

bioRxiv2023

Conserved long noncoding RNA TILAM promotes liver fibrosis through interaction with PML in hepatic stellate cells

Background & AimsFibrosis is the common endpoint for all forms of chronic liver injury, and progression of fibrosis leads to the development of end-stage liver disease. Activation of hepatic stellate cells (HSCs) and their transdifferentiation to myofibroblasts results in the accumulation of extracellular matrix (ECM) proteins that form the fibrotic scar. Long noncoding (lnc) RNAs regulate the activity of HSCs and may provide targets for fibrotic therapies. MethodsWe identified lncRNA TILAM as expressed near COL1A1 in human HSCs and performed loss-of-function studies in human HSCs and liver organoids. Transcriptomic analyses of HSCs isolated from mice defined the murine ortholog of TILAM. We then generated Tilam-deficient GFP reporter mice and quantified fibrotic responses to carbon tetrachloride (CCl4) and choline-deficient L-amino acid defined high fat diet (CDA-HFD). Co-precipitation studies, mass spectrometry, and gene expression analyses identified protein partners of TILAM. ResultsTILAM is conserved between human and mouse HSCs and regulates expression of ECM proteins, including collagen. Tilam is selectively induced in HSCs during the development of fibrosis in vivo. In both male and female mice, loss of Tilam results in reduced fibrosis in the setting of CCl4 and CDA-HFD injury models. TILAM interacts with promyelocytic leukemia protein (PML) to stabilize PML protein levels and promote the fibrotic activity of HSCs. ConclusionTILAM is activated in HSCs and interacts with PML to drive the development of liver fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end stage liver disease.

cell biology↗

bioRxiv2021

Nanchangmycin regulates FYN, FAK and ERK to control the fibrotic activity of hepatic stellate cells

Chronic liver injury causes fibrosis, characterized by the formation of scar tissue resulting from excessive accumulation of extracellular matrix (ECM) proteins. Hepatic stellate cell (HSC) myofibroblasts are the primary cell type responsible for liver fibrosis, yet there are currently no therapies directed at inhibiting the activity of HSC myofibroblasts. To search for potential anti-fibrotic drugs, we performed a high-throughput compound screen in primary human HSC myofibroblasts and identified 19 small molecules that induce HSC inactivation, including the polyether ionophore nanchangmycin (NCMC). NCMC induces lipid re-accumulation while reducing collagen expression, deposition of collagen in the extracellular matrix, cell proliferation, and migration. We find that NCMC increases cytosolic Ca2+ and reduces the phosphorylated protein levels of FYN, FAK, ERK1/2, HSP27 and STAT5B. Further, depletion of each of these kinases suppress COL1A1 expression. These studies reveal a signaling network triggered by NCMC to inactivate HSC myofibroblasts and reduce expression of proteins that compose the fibrotic scar. The identification of the antifibrotic effects of NCMC and the pathways by which NCMC inhibits fibrosis provides new tools and therapeutic targets to combat the development and progression of liver fibrosis.

cell biology↗

bioRxiv2020

Tet1 isoforms differentially regulate gene expression, synaptic transmission and memory in the mammalian brain.

The dynamic regulation of DNA methylation in post-mitotic neurons is necessary for memory formation and other adaptive behaviors. Ten-eleven translocation 1 (TET1) plays a part in these processes by oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby initiating active DNA demethylation. However, attempts to pinpoint its exact role in the nervous system have been hindered by contradictory findings, perhaps due in part, to a recent discovery that two isoforms of the Tet1 gene are differentially expressed from early development into adulthood. Here, we demonstrate that both the shorter transcript (Tet1S) encoding an N-terminally truncated TET1 protein and a full-length Tet1 (Tet1FL) transcript encoding canonical TET1 are co-expressed in the adult brain. We show that Tet1S is the predominantly expressed isoform, and is highly enriched in neurons, whereas Tet1FL is generally expressed at lower levels and more abundant in glia, suggesting their roles are at least partially cell-type specific. Using viral-mediated, isoform- and neuron-specific molecular tools, we find that Tet1S repression enhances, while Tet1FL impairs, hippocampal-dependent memory. In addition, the individual disruption of the two isoforms leads to contrasting changes in basal synaptic transmission and the dysregulation of unique gene ensembles in hippocampal neurons. Together, our findings demonstrate that each Tet1 isoform serves a distinct role in the mammalian brain.

neuroscience↗

bioRxiv2019

Biased M1 positive allosteric modulators reveal novel role of phospholipase D in M1-dependent rodent cortical plasticity

Highly selective positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach for the potential improvement of cognitive function in patients suffering from Alzheimers disease and schizophrenia. M1 PAM discovery programs have produced a structurally diverse range of M1 PAMs with distinct pharmacological properties, including different levels of agonist activity and differences in signal bias. This includes the recent discovery of novel biased M1 PAMs that can potentiate coupling of M1 to activation of phospholipase C but not phospholipase D (PLD). However, little is known about the role of PLD in M1 signaling in native systems and it is not clear whether biased M1 PAMs will display differences in modulating M1-mediated responses in native tissue. We now report a series of studies using novel PLD inhibitors and PLD knockout mice to show that PLD is necessary for the induction of M1-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Importantly, biased M1 PAMs that do not couple to PLD not only fail to potentiate orthosteric agonist-induced LTD but also block M1-dependent LTD in the PFC. In contrast, biased and non-biased M1 PAMs act similarly in potentiating M1-dependent electrophysiological responses that are PLD-independent. These findings demonstrate that PLD plays a critical role in the ability of M1 PAMs to modulate certain CNS functions and that biased M1 PAMs function differently in brain regions implicated in cognition.\n\nSummaryWe demonstrate a novel role of phospholipase D in M1-dependent rodent cortical plasticity and M1 PAMs that do not couple to phospholipase D have functionally distinct effects on cortical plasticity than non-biased M1 PAMs.

neuroscience↗

bioRxiv2019

lncRNA DIGIT and BRD3 protein form phase-separated condensates to regulate endoderm differentiation

Gene programs that control differentiation are regulated through the interplay between DNA, RNA, and protein. Cooperation among these fundamental cellular components can occur through highly structured interactions connecting domains formed by specific sequences of nucleotides, ribonucleotides, and/or amino acids and also through the assembly of biomolecular condensates. Here, we show that endoderm differentiation is regulated through the interaction of the long noncoding (lnc) RNA DIGIT and the bromodomain and extra-terminal (BET) domain family protein BRD3. BRD3 forms phase-separated condensates that contain DIGIT, occupies enhancers of endoderm transcription factors, and is required for endoderm differentiation. Purified BRD3 binds to acetylated histone H3 lysine 18 (H3K18ac) in vitro and occupies regions of the genome enriched in H3K18ac during endoderm differentiation, including the key transcription factors that regulate endoderm differentiation. DIGIT is also enriched in regions of H3K18ac, and depletion of DIGIT results in decreased recruitment of BRD3 to these regions. Our findings support a model where cooperation between DIGIT and BRD3 at regions of H3K18ac regulates the transcription factors that drive endoderm differentiation and suggest a broader role for protein-lncRNA phase-separated condensates as regulators of transcription in development.

molecular biology↗