Biology subjects

Saw, A. K.

Publications and source records attributed to Saw, A. K..

4 recordsLinked to original sources

bioRxiv2026

Spatially Anchored Regulatory State Inference in Melanoma

Spatial transcriptomics (ST) captures gene expression within tissue architecture but lacks direct regulatory information, while single-cell multiome assays profile transcriptional and chromatin states without spatial context. We present a framework for spatially anchored regulatory inference that integrates Visium ST with single-cell multiome data to infer spatially resolved regulatory programs. Building upon GraphST, we introduce spatially regularized cell-to-spot mapping and propagate chromatin accessibility and transcription factor motif activity into tissue space. Regulatory analysis is performed at the spatial domain level via joint differential expression and accessibility testing, along with quantitative concordance assessment. Applied to melanoma tissue sections, the framework reveals spatially localized regulatory programs and shows that assignment strategy substantially affects downstream regulatory stability. This modular approach enables interpretable gene-, peak-, and transcription factor-level outputs for multimodal spatial analysis.

bioinformatics↗

bioRxiv2026

Fasting primes small intestinal regeneration after damage via a microbiome metabolite chromatin axis

Fasting enhances small intestinal regeneration after radiation but the contribution of the gut microbiome to this process remains uncharacterized. We identify Akkermansia muciniphila (AKK) as a key mediator of this response. AKK was enriched in fasted mice and its antibiotic depletion abrogated radioprotection whereas reintroduction restored both organismal survival and intestinal integrity. Fasting elevated propionic acid, consistent with AKKs metabolic output. AKK-conditioned medium and propionate induced histone H3 acetylation in intestinal stem cell cultures while in vivo fasting induced AKK-dependent H3K27ac and H3K9ac, remodeling promoter-enhancer landscapes in crypt epithelial cells. Epigenetic profiling revealed a rewired core regulatory program enriched for pioneer transcription factors (Foxa, Gata, Klf), architectural organizers (Ctcf, Boris), and lineage-defining and metabolic regulators (Cdx2, Hnf4). This program supports expansion of a population of persister stem cells characterized by open chromatin accessibility at key stem and regenerative-associated loci including Clu, Olfm4, Lgr5, Ascl2, Lrig1, Sox9, Rnf43, and Axin2. These findings define a fasting-induced microbiome-metabolite-chromatin axis that epigenetically primes highly plastic persister stem cells for rapid regeneration of the intestinal epithelium following radiation-induced injury. Significance StatementFasting changes the gut microbiome, but how these changes help the body recover from damage is not well understood. We found that fasting increases a helpful bacterium, Akkermansia muciniphila, which produces propionate, which drives epigenetic changes by modifying histones and regulating gene activity. These changes promote the expansion of persister stem cells that help the intestine recover after radiation. This study shows how fasting and gut bacteria work together to protect healthy tissue and suggests that diet or microbial treatments could help reduce side effects of cancer radiotherapy.

cell biology↗

bioRxiv2025

Reprogramming of Cellular Plasticity via ETS and MYC Core-regulatory Circuits During Response to MAPK Inhibition in BRAF-mutant Colorectal Cancer

BackgroundAberrant enhancer dynamics play a critical role in the initiation and progression of colorectal cancer (CRC). BRAFV600E-mutated metastatic CRC may be a unique subtype, exhibiting a strong epigenetic phenotype. Interestingly, bromodomain 2, a reader protein for H3K27ac-marked enhancers, was found to be synthetically lethal in CRC with BRAF + EGFR inhibition. DesignWe evaluated the effectiveness of targeting aberrant enhancers with bromodomain and extraterminal (BET) + MAPK pathway inhibitors in patient-derived xenograft models of metastatic CRC, followed by comprehensive profiling of transcriptomic and chromatin dynamics upon BET inhibitor combination treatment. ResultsThe combination of BET and standard MAPK inhibitors has demonstrated improved efficacy against BRAFV600E CRC and selective improvements against RAS-mutant CRC in vivo. We showed that BET + MAPK inhibition induced a profound downregulation of the MAPK signaling pathway compared to MAPK inhibition alone. The loss of activation signal on enhancers, as determined by H3K27ac, led to dysregulation of core-regulatory circuitries of CRC, especially loss of the auto-regulatory mechanism of the MAPK downstream E26 transformation-specific transcription factor family. Single nucleus multiome (RNA + ATAC) sequencing further distinguished differential transcriptomic and chromatin dynamics at cell type levels. Profound downregulation of well-differentiated cell types confirmed deep inhibition of MAPK signaling and downstream transcription factors. On the other hand, dedifferentiated cell populations were abundant after MAPK or combination inhibition, suggesting therapy-induced cell state switching and adaptation. ConclusionWe are evaluating BET + BRAF + EGFR inhibition in patients with treatment-refractory BRAFV600E metastatic CRC. ClinicalTrial.gov identifier: NCT06102902. What is already known on this topicEnhancer aberrations emerge as critical epigenetic features in the progression of colorectal cancer (CRC). However, the dynamics of active enhancer and the therapeutic potential of enhancer blockade, particularly in CRC tumors with BRAFV600E mutation, is not well understood. What this study addsThis study demonstrates improved efficacy of BET inhibitor combination therapies in diverse patient-derived models and reveals epigenetic reprogramming driven cellular plasticity in BRAFV600E-mutated CRC. How this study might affect research, practice or policyOur findings support treatment with BET + BRAF + EGFR inhibitors for patients with BRAFV600E-mutant mCRC [NCT06102902]. This study also highlights the potential of combining epigenetic agents to standard targeted therapy, offering a novel treatment option for this subset of patients.

cancer biology↗

bioRxiv2022

Combined promoter-capture Hi-C and Hi-C analysis reveals a fine-tuned regulation of 3D chromatin architecture in colorectal cancer

Hi-C is a widely used method for profiling chromosomal interactions in the 3-dimensional context. Due to limitations on the depth of sequencing, the resolution of most Hi-C datasets is often insufficient for scoring fine-scale interactions. We therefore used promoter-capture Hi-C (PCHi-C) data for mapping these subtle interactions. From multiple colorectal cancer (CRC) studies, we combined PCHi-C with Hi-C datasets to understand the dynamics of chromosomal interactions from cis regulatory elements to topologically associated domain (TAD)-level, enabling detection of fine-scale interactions of disease-associated loci within TADs. Our integrated analyses of PCHi-C and Hi-C datasets from CRC cell lines along with histone modification landscape and transcriptome signatures highlight significant genomic structural instability and their association with tumor-suppressive transcriptional programs. Such analyses also yielded nine dysregulated genes. Transcript profiling revealed a dramatic increase in their expression in CRC cell lines as compared to NT2D1 human embryonic carcinoma cells, supporting the predictions of our bioinformatics analysis. We further report increased occupancy of activation associated histone modifications H3K27ac and H3K4me3 at the promoter regions of the targets analyzed. Our study provides deeper insights into the dynamic 3D genome organization in CRC and identification of affected genes which may serve as potential biomarkers for CRC. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/515643v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@11a9fc8org.highwire.dtl.DTLVardef@f01eb4org.highwire.dtl.DTLVardef@6ff038org.highwire.dtl.DTLVardef@103fc24_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗