Biology subjects

Park, J.-I.

Publications and source records attributed to Park, J.-I..

4 recordsLinked to original sources

bioRxiv2022

PCLAF-DREAM Drives Alveolar Cell Plasticity for Lung Regeneration

Spatiotemporal control of stem and progenitor cells is essential for lung regeneration, the failure of which leads to lung disease. However, the mechanism of alveolar cell plasticity during regeneration remains elusive. We previously found that PCLAF remodels the DREAM complex for cell cycle re-entry. PCLAF expression is specifically enriched in proliferating lung progenitor cells, along with the DREAM target genes by lung damage. Genetic ablation of Pclaf inhibited alveolar type I (AT1) cell regeneration from alveolar type II (AT2) cells, inducing lung fibrosis. Mechanistically, the PCLAF-DREAM complex directly transactivates CLIC4, promoting TGF-{beta} signaling that regulates the balance between AT1 and AT2 cells. Furthermore, a drug candidate that mimics the PCLAF-DREAM transcriptional signatures for lung regeneration was identified and validated in organoids and mice. Our study unveils an unexpected role of the PCLAF-DREAM axis in controlling alveolar cell plasticity for lung regeneration and proposes a viable option for lung fibrosis prevention. One Sentence SummaryPCLAF-DREAM-driven alveolar cell plasticity is crucial for lung regeneration and can be pharmacologically targeted as a therapeutic strategy for lung fibrosis.

cell biology↗

bioRxiv2022

WNT5A-RHOA axis is a new vulnerability in small-cell lung cancer

WNT signaling presents an attractive target for cancer therapy due to its widespread oncogenic role. However, the molecular players involved in WNT signaling and the impact of their perturbation remain unknown for numerous recalcitrant cancers including small-cell lung cancer (SCLC). Here we show that beta-catenin, a master mediator of canonical WNT signaling, is not required for SCLC development in genetically engineered mouse models (GEMMs) and its transcriptional program is largely silenced during tumor development. Instead, inactivation of p130 in SCLC cells induces expression of WNT5A, a ligand for beta-catenin-independent WNT pathways. WNT5A is both sufficient and required for SCLC development and cell proliferation and selectively induces Rhoa transcription and activates RHOA protein to drive SCLC. Rhoa knockout suppresses SCLC development in vivo, and chemical perturbation of RHOA selectively inhibits SCLC cell proliferation. These findings suggest a novel requirement for the WNT5A-RHOA axis in SCLC that is distinct from other noncanonical WNT pathways. This vulnerability of p130-WNT5A-RHOA pathway provides critical insight into the development of novel therapeutic strategies for the recalcitrant cancer, as well as the stratification of patients who may benefit from them. This study also sheds new light on the heterogeneity of WNT signaling and the molecular determinants of its cell-type specificity.

cancer biology↗

bioRxiv2021

High-throughput imaging of Caenorhabditis elegans aging using collective activity monitoring

The genetic manipulability and short lifespan of C. elegans make it an important model for aging research. Widely applied methods for measurements of worm aging based on manual observation are labor intensive and low-throughput. Here, we describe the Worm Collective Activity Monitoring Platform (WormCamp), a system for assaying aging in C. elegans by monitoring activity of populations of worms in standard 24-well plates. We show that metrics based on the rate of decline in collective activity can be used to estimate the average lifespan and locomotor healthspan in the population. Using the WormCamp, we assay a panel of highly divergent natural isolates of C. elegans and show that both lifespan and locomotor healthspan display substantial heritability. To facilitate analysis of large numbers of worms, we developed a robotic imaging system capable of simultaneous automated monitoring of activity, lifespan, and locomotor healthspan in up to 2,304 populations containing a total of ~90,000 animals. We applied the automated system to conduct a large-scale RNA interference screen for genes that affect lifespan and locomotor healthspan. The WormCamp system is complementary to other current automated methods for assessing C. elegans aging and is well suited for efficiently screening large numbers of conditions.

bioengineering↗

bioRxiv2021

Yap/Taz-Activated Expansion of Tert-Expressing Acinar Cells Are Required for Pancreatic Regeneration

The expression of TERT (telomerase reverse transcriptase) has been implicated in stem and progenitor cells, which are essential for tissue homeostasis and regeneration. However, the roles of TERT-expressing cells in the pancreas remain elusive. Employing genetically engineered Tert knock-in mouse model, herein, we located a rare population of Tert+ acinar cells. While Tert+ cells are quiescent in normal conditions, acinar cell injury leads to mitotic activation of Tert+ cells and subsequent generation of new acinar cells. Moreover, the genetic ablation of Tert+ cells impairs pancreatic regeneration. We further found that Yap/Taz activation is required for the expansion of Tert+ acinar cells. Our results identified Tert+ acinar cells as a distinct subset of acinar cells, which contributes to pancreatic regeneration via Yap/Taz activation.

cell biology↗