Biology subjects

Li, S. K.

Publications and source records attributed to Li, S. K..

4 recordsLinked to original sources

bioRxiv2025

Chromatin remodeling integrates vertebrate body axis elongation and cell fate determination

The effective elongation of the vertebrate body axis depends on the precise coordination of cell movements and cell fate determination within the posterior tailbud region. However, the specific biological determinant that integrates these cellular processes during vertebrate tail bud elongation has remained unclear. Here, we demonstrate that the spatiotemporal heterogeneity of chromatin condensation states governs both cell fate and cell motility within the mesodermal progenitor zone (MPZ) and the presomitic mesoderm (PSM) during zebrafish tail bud elongation. By integrating biological experiments with computational modeling, we reveal that nuclear volume heterogeneity, mediated by chromatin remodeling, acts as an active driver of collective cell migration. Reducing chromatin condensation heterogeneity in the MPZ through modulation of chromatin modifications impairs collective cell movements and delays tailbud elongation. Single cell ATAC-seq and RNA-seq analyses reveal that global chromatin accessibility heterogeneity and region-specific chromatin remodeling differences in the PSM and MPZ are functionally associated with gene expression pathways involving in cell lineage specification. These findings establish a molecular connection between cell fate determination and tissue-scale cellular dynamics. Collectively, our findings unveil a unifying framework for understanding the coordination of cell fate determination and large-scale cellular movements during tissue morphogenesis.

developmental biology↗

bioRxiv2025

Rational design of potent small molecule SMARCA2/A4 (BRM/BRG1) degraders acting via the recruitment of FBXO22

Target-anchored monovalent degraders are more drug-like than their bivalent counterparts, Proteolysis Targeting Chimeras (PROTACs), while offering greater target specificity control than the E3 ligase-anchored monovalent degraders, also known as molecular glues. However, their discovery has typically been serendipitous, and the rules governing their identification remain unclear. This study focused on the intentional discovery of SMARCA2/A4 monovalent degraders using a library based on SMARCA2/A4 bromodomain-binding ligands. Compound G-6599 emerged as a lead candidate, showing exceptional degradation potency and specificity for SMARCA2/A4. Mechanistic studies revealed that G-6599 operates through the ubiquitin-proteasome pathway and the E3 ligase FBXO22. G-6599 was shown to promote ternary complex formation between SMARCA2 and FBXO22 involving covalent conjugation to a cysteine residue on the latter. Unlike other recently identified FBXO22-dependent degraders, it does not require biotransformation. The selective degradation ability of G-6599, along with its unique mechanism, highlights the therapeutic potential of target-anchored monovalent degraders.

cancer biology↗

bioRxiv2022

Long-term Antibody Release Polycaprolactone (PCL) Capsule and the Release Kinetics In Natural and Accelerated Degradation

Although therapy using monoclonal antibodies (mAbs) has been steadily successful over the last 20 years, the means of delivery of mAbs has not been optimized, especially for long-term delivery. Frequent injections or infusions have been current standard of care. In this study, we have developed a long-term antibody biodegradable implant using a porous polycaprolactone (PCL) capsule. It released Bevacizumab (Bev) slowly for 8 months to date. The Bev release kinetics fit a drug release model with experimental data of the diffusion coefficient and partition coefficient through the polymer capsule. Since screening drug release profiles for the long-term (> 6 months) is time consuming, an accelerated degradation method was used after validating characteristics of the PCL capsule in natural and accelerated degradation conditions. The correlation of time period between the natural and the accelerated degradation was determined. Overall, the study suggests mAbs can be released from a porous PCL capsule without an effect of the polymer degradation over the long period (~ 6 months) and the long-term release kinetics can be determined by the accelerated degradation within 14 days.

bioengineering↗

bioRxiv2021

Mechanically Sensitive HSF1 is a Key Regulator of Left-Right Symmetry Breaking in Zebrafish Embryos

The left-right symmetry breaking of vertebrate embryos requires fluid flow (called nodal flow in zebrafish). However, the molecular mechanisms that mediate the asymmetric gene expression regulation under nodal flow remain elusive. In this paper, we report that heat shock factor 1 (HSF1) is asymmetrically activated in the Kuppfers vesicle at the early stage of zebrafish embryos in the presence of nodal flow. Deficiency in HSF1 expression caused a significant situs inversus and disrupted gene expression asymmetry of nodal signaling proteins in zebrafish embryos. Further studies demonstrated that HSF1 could be immediately activated by fluid shear stress. The mechanical sensation ability of HSF1 is conserved in a variety of mechanical stimuli in different cell types. Moreover, cilia and the Ca2+-Akt signaling axis are essential for the activation of HSF1 under mechanical stress in vitro and in vivo. Considering the conserved expression of HSF1 in organisms, these findings unveil a fundamental mechanism of gene expression regulation triggered by mechanical clues during embryonic development and other physiological and pathological transformations.

developmental biology↗