Biology subjects

Guan, K.-L.

Publications and source records attributed to Guan, K.-L..

5 recordsLinked to original sources

bioRxiv2024

Spatiotemporally restricted Hippo signalings instruct the fate and maturation of hepatobiliary cells

The Hippo pathway is an evolutionary conserved signaling cascade involved in organ size control and tumorigenesis, but its cellular functions and regulatory mechanisms are not fully understood. Recently, we have defined two independent modules (HPO1 and HPO2) in the Hippo signaling network. Here, by using spatially resolved transcriptomic and imaging analysis of mouse livers with defective Hippo signaling, we show that HPO1 and HPO2 operate in distinct cells at different developmental stages to regulate the fate and maturation of liver parenchymal cells. HPO1 controls the maturation of hepatocytes postnatally, and its perturbation leads to the expansion of immature hepatocytes (imHep). HPO2, on the other hand, regulates the maturation of cholangiocytes perinatally, and its ablation results in the accumulation of immature cholangiocytes (imCho2) identical to developing ductal plate cells. Moreover, the inactivation of HPO1 or HPO2 causes the conversion of hepatocytes into immature cholangiocytes (imCho1). These immature cells are also observed in regenerating livers following different damages. In contrast, deletion of Yap/Taz encoding downstream effectors of the Hippo pathway accelerates liver maturation and promotes cell death. These findings suggest that the spatiotemporally restricted Hippo signaling modules act as checkpoints in liver development and may coordinate cell proliferation and maturation to ensure proper liver size and function.

cell biology↗

bioRxiv2024

IGF2 mediates Hippo signaling to control liver size

The Hippo pathway is a central mechanism in organ size control, but the mediator for its function remains elusive. Here, we show that the expression of insulin-like growth factor II (IGF2) is directly induced by YAP/TAZ transcription cofactors of the Hippo pathway in a developmental stage- and cell type-specific manner. In mouse livers, Igf2 expression is sustained by YAP/TAZ in hepatoblasts and immature hepatocytes at fetal and neonatal stages, coupling with rapid cell proliferation and liver size expansion, whereas turned off in matured hepatocytes following YAP/TAZ inactivation to prevent liver overgrowth. In contrast, YAP/TAZ fails to regulate Igf2 expression in cholangiocytes and diverse liver mesenchymal cells where epigenetic barriers, including DNA and histone methylation, are implanted near Igf2 promoters. Furthermore, IGF2 activates IGF1R signaling and promotes normal and neoplastic liver growth, while the inactivation of IGF2 or IGF1R effectively blocks YAP/TAZ-induced hepatomegaly and hepatoblastoma. In conclusion, our findings reveal that IGF2 is a bona fide mediator of the Hippo pathway, indicating a fundamental role of the Hippo-IGF2-IGF1R signaling axis in organ size regulation and malignancies.

cell biology↗

bioRxiv2024

Human Satellite 3 DNA encodes megabase-scale transcription factor binding platforms

Eukaryotic genomes frequently contain large arrays of tandem repeats, called satellite DNA. While some satellite DNAs participate in centromere function, others do not. For example, Human Satellite 3 (HSat3) forms the largest satellite DNA arrays in the human genome, but these multi-megabase regions were almost fully excluded from genome assemblies until recently, and their potential functions remain understudied and largely unknown. To address this, we performed a systematic screen for HSat3 binding proteins. Our work revealed that HSat3 contains millions of copies of transcription factor (TF) motifs bound by over a dozen TFs from various signaling pathways, including the growth-regulating transcription effector family TEAD1-4 from the Hippo pathway. Imaging experiments show that TEAD recruits the co-activator YAP to HSat3 regions in a cell-state specific manner. Using synthetic reporter assays, targeted repression of HSat3, inducible degradation of YAP, and super-resolution microscopy, we show that HSat3 arrays can localize YAP/TEAD inside the nucleolus, enhancing RNA Polymerase I activity. Beyond discovering a direct relationship between the Hippo pathway and ribosomal DNA regulation, this work demonstrates that satellite DNA can encode multiple transcription factor binding motifs, defining an important functional role for these enormous genomic elements.

cell biology↗

bioRxiv2019

Decoding WW Domain Tandem-mediated Target Recognitions in Tissue Growth and Cell Polarity

WW domain tandem-containing proteins such as KIBRA, YAP, and MAGI play critical roles in cell growth and polarity via binding to and positioning target proteins in specific subcellular regions. An immense disparity exists between promiscuity of WW domain-mediated target bindings and specific roles of WW domain scaffold proteins in cell growth regulation. Here, we discovered that WW domain tandems of KIBRA and MAGI, but not YAP, bind to specific target proteins with extremely high affinity and exquisite specificity. Via systematic structural biology and biochemistry approaches, we decoded the target binding rules of WW domain tandems from cell growth regulatory proteins and uncovered a list of previously unknown WW tandem binding proteins such as {beta}-Dystroglycan, JCAD, and PTPN21. The WW tandem-mediated target recognition mechanisms elucidated here can guide functional studies of WW domain proteins in cell growth and polarity as well as in other cellular processes including neuronal synaptic signaling.

biophysics↗

bioRxiv2019

YAP/TAZ as a Novel Regulator of cell volume

How mammalian cells regulate their physical size is currently poorly understood, in part due to the difficulty of accurately quantifying cell volume in a high throughput manner. Here, using the fluorescence exclusion method, we demonstrate that the mechanosensitive transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are novel regulators of single cell volume. We report that the role of YAP/TAZ in cell volume regulation must go beyond its influence on total cell cycle duration or the cell shape to explain the observed changes in volume. Moreover, for our experimental conditions, volume regulation by YAP/TAZ is independent of mTOR. Instead, we find YAP/TAZ directly impacts the cell division volume. Based on the idea that YAP/TAZ is a mechanosensor, we find that inhibiting the assembly of myosin and cell tension slows cell cycle progression from G1 to S. These results suggest that YAP/TAZ and the Hippo pathway may be modulating cell volume in combination with cytoskeletal tension during cell cycle progression.

bioengineering↗