Biology subjects

MENG, L.

Publications and source records attributed to MENG, L..

3 recordsLinked to original sources

bioRxiv2025

Loss of HNF1b drives pancreatic Intraductal Papillary Mucinous Neoplasms (IPMN) initiation

BackgroundIntraductal papillary mucinous neoplasms (IPMNs) are clinically detectable precursors of pancreatic adenocarcinoma, yet the mechanisms initiating their development remain poorly defined. Although KRAS mutations are highly frequent in human IPMNs, KRAS activation in pancreatic ductal cells alone fails to recapitulate IPMN development in murine models, indicating that additional tumor-suppressive mechanisms must be overcome. ObjectiveThe objective was to determine whether loss of the transcription factor HNF1B predisposes to initiation of IPMN. DesignWe assessed HNF1B nuclear expression and promoter methylation in resected human IPMN specimens. To model IPMN initiation, we generated mice with ductal-specific inactivation of Hnf1b, alone or combined with KRASG12D. Ductal organoids and RNA-sequencing were used to investigate molecular mechanisms. Transcriptomic analyses were also performed on human IPMN surgical specimens. MRI from germline HNF1B mutation/deletion carriers was re-evaluated for IPMN prevalence. ResultsHuman IPMNs showed loss of HNF1B by immunochemistry, with enrichment to promoter methylation that increased with dysplasia grade. The KHC model recapitulated the key features of IPMN development including ductal dilation, high proliferation, papillary architecture and mucin production. Loss of Hnf1b together with Kras activation induced loss of primary cilia, cellular reprogramming and engaged oncogenic YAP and Wnt/{beta}-catenin signaling, similar to human IPMNs. Moreover, germline HNF1B carriers exhibited a markedly increased prevalence of branch-duct IPMN. ConclusionHNF1B functions as a tumor-suppressive gatekeeper of pancreatic ductal cells. These findings highlight HNF1B inactivation as a potential biomarker and therapeutic entry point for early interception of IPMN-driven pancreatic cancer. They also have implications for the surveillance of HNF1B-syndrome.

pathology↗

bioRxiv2022

Random folding drives the emergence of topologically associating domains in chromatin three-dimensional structure

Domains are units of genome organization. Due to the seemingly irreconcilable difference between topologically associating domains (TADs) revealed by population-based biochemical studies and domains (sTADs) by single-cell imaging, finding a mechanism that simultaneously shape TADs and sTADs is challenging. Here we propose that TADs and sTADs are underlied by random folding of chromatin fiber heterogeneous in DNA density. On the hypothesis, we develop a model, termed RCHC, to yield chromatin structure ensemble from chromatin accessibility data. Calculated ensemble enables our hypothesis to be validated by population-based and single-cell experiments. Our simulation confirms the independence between domain and compartment structures in genome organization and shows that RCHC can predict the chromatin reorganization during differentiation. We mechanistically prove that genome is organized randomly with biases introduced by DNA-encoded information. One-Sentence SummaryThe TADs emergence is underlied by random folding of heterogeneous chromatin fiber carrying nucleosome occupancy information.

genomics↗

bioRxiv2020

Si-C: method to infer biologically valid super-resolution intact genome structure from single-cell Hi-C data

There is a strong demand for the methods that can efficiently reconstruct biologically valid super-resolution intact genome 3D structures from sparse and noise single-cell Hi-C data. Here, we developed Single-Cell Chromosome Conformation Calculator (Si-C) within the Bayesian theory framework and applied this approach to reconstruct intact genome 3D structures from the single-cell Hi-C data of eight G1-phase haploid mouse ES cells. The inferred 100-kb and 10-kb structures consistently reproduce the known conserved features of chromatin organization revealed by independent imaging experiments. The analysis of the 10-kb resolution 3D structures revealed cell-to-cell varying domain structures in individual cells and hyperfine structures in domains, such as loops. An average of 0.2 contact reads per divided bin is sufficient for Si-C to obtain reliable structures. The valid super-resolution structures constructed by Si-C demonstrates the potential for visualizing and investigating interactions between all chromatin loci at genome scale in individual cells.

bioinformatics↗