Biology subjects

Choppavarapu, L.

Publications and source records attributed to Choppavarapu, L..

3 recordsLinked to original sources

bioRxiv2024

Hi-C profiling in tissues reveals 3D chromatin-regulated breast tumor heterogeneity and tumor-specific looping-mediated biological pathways

Current knowledge in three-dimensional (3D) chromatin regulation in normal and disease states was mostly accumulated through Hi-C profiling in in vitro cell culture system. The limitations include failing to recapitulate disease-specific physiological properties and often lacking clinically relevant disease microenvironment. In this study, we conduct tissue-specific Hi-C profiling in a pilot cohort of 12 breast tissues comprising of two normal tissues (NTs) and ten ER+ breast tumor tissues (TTs) including five primary tumors (PTs), and five tamoxifen-treated recurrent tumors (RTs). We find largely preserved compartments, highly heterogeneous topological associated domains (TADs) and intensively variable chromatin loops among breast tumors, demonstrating 3D chromatin-regulated breast tumor heterogeneity. Further cross-examination identifies RT-specific looping-mediated biological pathways and suggests CA2, an enhancer-promoter looping (EPL)-mediated target gene within the bicarbonate transport metabolism pathway, might play a role in driving the tamoxifen resistance. Remarkably, the inhibition of CA2 not only impedes tumor growth both in vitro and in vivo, but also reverses chromatin looping. Our study thus yields significant mechanistic insights into the role and clinical relevance of 3D chromatin architecture in breast cancer endocrine resistance.

cancer biology↗

bioRxiv2023

Reprogramming of 3D chromatin domains by antagonizing the β-catenin/CBP interaction attenuates insulin signaling in pancreatic cancer

The therapeutic potential of targeting the {beta}-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a {beta}-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this {beta}-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the {beta}-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of the functional crosstalk between antagonizing the {beta}-catenin/CBP interaction effect changes in 3D chromatin architecture and thereby gene expression and downstream effects remains to be elucidated. Here we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after the treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1, a key insulin signaling gene, significantly impede pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.

cancer biology↗

bioRxiv2023

Integration of scHi-C and scRNA-seq data defines distinct 3D-regulated and biological-context dependent cell subpopulations

An integration of 3D chromatin structure and gene expression at single-cell resolution has yet been demonstrated. Here, we develop a computational method, a multiomic data integration (MUDI) algorithm, which integrates scHi-C and scRNA-seq data to precisely define the 3D-regulated and biological-context dependent cell subpopulations or topologically integrated subpopulations (TISPs). We demonstrate its algorithmic utility on the publicly available and newly generated scHi-C and scRNA-seq data. We then test and apply MUDI in a breast cancer cell model system to demonstrate its biological-context dependent utility. We found the newly defined topologically conserved associating domain (CAD) is the characteristic single-cell 3D chromatin structure and better characterizes chromatin domains in single-cell resolution. We further identify 20 TISPs uniquely characterizing 3D-regulated breast cancer cellular states. We reveal two of TISPs are remarkably resemble to high cycling breast cancer persister cells and chromatin modifying enzymes might be functional regulators to drive the alteration of the 3D chromatin structures. Our comprehensive integration of scHi-C and scRNA-seq data in cancer cells at single-cell resolution provides mechanistic insights into 3D-regulated heterogeneity of developing drug-tolerant cancer cells.

bioinformatics↗