Biology subjects

Lin, C. Y.

Publications and source records attributed to Lin, C. Y..

7 recordsLinked to original sources

bioRxiv2024

Growth generates a hyperdisordered pattern of chromatophores on squid skin

While the physics of disordered packing in non-growing systems is well understood, unexplored phenomena can emerge when packing takes place in growing domains. We study the arrangements of pigment cells (chromatophores) on squid skin as a biological example of a packed system on an expanding surface. We find that relative density fluctuations in cell numbers grow with spatial scale. We term this behavior "hyperdisordered", in contrast with hyperuniform behavior in which relative fluctuations tend to zero at large scale. We find that hyperdisordered scaling, akin to that of a critical system, is quantitatively reproduced by a model in which hard disks are randomly inserted in a homogeneously growing surface. In addition, we find that chromatophores increase in size during animal development, but maintain a stationary size distribution. The physical mechanisms described in our work may apply to a broad class of growing dense systems.

biophysics↗

bioRxiv2022

Cellular Maturation of Oligodendrocytes is Governed by Transient Gene Melting

Pluripotent stem cells (PSCs) provide an unlimited source for generating somatic cell types. However, generating fully mature cells constitutes a bottleneck for realizing their full potential in research and medicine. Here, we report a transcriptional mechanism that governs the timing of cellular maturation in post-mitotic oligodendrocytes. During differentiation of PSCs to oligodendrocytes, the transcription factor SOX6 redistributes from nearly all super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit gene melting, a process of extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggestive that failed maturation may contribute to limited myelin regeneration in disease. Collectively, our finding that maturation rate is controlled by transient transcriptional clusters may inform approaches to accelerate the generation and regeneration of mature cell types. HIGHLIGHTSO_LITranscription factors (TFs) can act as gatekeepers of post-mitotic cellular maturation C_LIO_LIIn oligodendrocytes, clustering of SOX6 controls the immaturity program through transient gene melting C_LIO_LISuppressing SOX6 deactivates immaturity genes and unlocks oligodendrocyte maturation C_LIO_LISOX6 immaturity signature is enriched in oligodendrocytes in multiple sclerosis patients C_LI

developmental biology↗

bioRxiv2021

Transcriptional plasticity drives leukemia immune escape

Relapse of acute myeloid leukemia (AML) after allogeneic bone marrow transplantation (alloSCT) has been linked to immune evasion due to reduced expression of major histocompatibility complex class II (MHC-II) proteins through unknown mechanisms. We developed CORENODE, a computational algorithm for genome-wide transcription network decomposition, that identified the transcription factors (TFs) IRF8 and MEF2C as positive regulators and MYB and MEIS1 as negative regulators of MHC-II expression in AML cells. We show that reduced MHC-II expression at relapse is transcriptionally driven by combinatorial changes in the levels of these TFs, acting both independently and through the MHC-II coactivator CIITA. Beyond the MHC-II genes, MYB and IRF8 antagonistically regulate a broad genetic program responsible for cytokine signaling and T-cell stimulation that displays reduced expression at relapse. A small number of cells with altered TF levels and silenced MHC-II expression are present at the time of initial leukemia diagnosis, likely contributing to eventual relapse. Our findings reveal an adaptive transcriptional mechanism of AML evolution after allogenic transplantation whereby combinatorial fluctuations of TF levels under immune pressure result in selection of cells with a silenced T-cell stimulation program.

genomics↗

bioRxiv2021

A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia

A small set of lineage-restricted transcription factors (TFs), termed core regulatory circuitry (CRC), control cell identity and malignant transformation. Here, we integrated gene dependency, chromatin architecture and TF perturbation datasets to characterize 31 core TFs in acute myeloid leukemia (AML). Contrary to a widely accepted model, we detected a modular CRC structure with hierarchically organized, partially redundant and only sparsely interconnected modules of core TFs controlling distinct genetic programs. Rapid TF degradation followed by measurement of genome-wide transcription rates revealed that core TFs directly regulate dramatically fewer genes than previously assumed. Leukemias carrying KMT2A (MLL) rearrangements depend on the IRF8/MEF2 axis to directly enforce expression of the key oncogenes MYC, HOXA9 and BCL2. Our datasets provide an evolving model of CRC organization in human cells, and a resource for further inquiries into and therapeutic targeting of aberrant transcriptional circuits in cancer.

genomics↗

bioRxiv2019

Dynamic chromatin targeting of BRD4 stimulates cardiac fibroblast activation

Small molecule inhibitors of the acetyl-histone binding protein BRD4 have been shown to block cardiac fibrosis in pre-clinical models of heart failure (HF). However, the mechanisms by which BRD4 promotes pathological myocardial fibrosis remain unclear. Here, we demonstrate that BRD4 functions as an effector of TGF-{beta} signaling to stimulate conversion of quiescent cardiac fibroblasts into Periostin (Postn)-positive cells that express high levels of extracellular matrix. BRD4 undergoes stimulus-dependent, genome-wide redistribution in cardiac fibroblasts, becoming enriched on a subset of enhancers and super-enhancers, and leading to RNA polymerase II activation and expression of downstream target genes. Employing the SERTA domain-containing protein 4 (Sertad4) locus as a prototype, we demonstrate that dynamic chromatin targeting of BRD4 is controlled, in part, by p38 mitogen-activated protein kinase, and provide evidence of a novel function for Sertad4 in TGF-{beta}-mediated cardiac fibroblast activation. These findings define BRD4 as a central regulator of the pro-fibrotic cell state of cardiac fibroblasts, and establish a signaling circuit for epigenetic reprogramming in HF.

molecular biology↗

bioRxiv2019

Extracellular Pgk1 enhances neurite outgrowth of motoneurons through Nogo66-independent targeting of NogoA

NogoA inhibits neurite outgrowth of motoneurons (NOM) through interaction with its receptors, Nogo66/NgR. Inhibition of Nogo receptors rescues NOM, but not to the extent exhibited by NogoA-knockout mice, suggesting the presence of other pathways. We found that NogoA-overexpressing muscle cells reduced phosphoglycerate kinase 1 (Pgk1) secretion, resulting in inhibiting NOM. Apart from its glycolytic role and independent of the Nogo66 pathway, extracellular Pgk1 stimulated NOM by triggering a reduction of p-Cofilin-S3, a growth cone collapse marker, through decreasing a novel Rac1-GTP/p-Pak1-T423/p-P38-T180/p-MK2-T334/p-Limk1-S323/p-Cofilin-S3 molecular pathway. Not only did supplementary Pgk1 enhance NOM in defective cells, but injection of Pgk1 rescued denervation in muscle-specific NogoA-overexpression of zebrafish and an Amyotrophic Lateral Sclerosis mouse model, SOD1-G93A. Thus, Pgk1 secreted from muscle is detrimental to motoneuron synapse growth and maintenance.

developmental biology↗

bioRxiv2018

Identification of candidate master transcription factors within enhancer-centric transcriptional regulatory networks

Regulation of gene expression through binding of transcription factors (TFs) to cis-regulatory elements is highly complex in mammalian cells. Genome-wide measurement technologies provide new means to understand this regulation, and models of TF regulatory networks have been built with the goal of identifying critical factors. Here, we report a network model of transcriptional regulation between TFs constructed by integrating genomewide identification of active enhancers and regions of focal DNA accessibility. Network topology is confirmed by published TF ChIP-seq data. By considering multiple methods of TF prioritization following network construction, we identify master TFs in well-studied cell types, and these networks provide better prioritization than networks only considering promoter-proximal accessibility peaks. Comparisons between networks from similar cell types show stable connectivity of most TFs, while master regulator TFs show dramatic changes in connectivity and centrality. Applying this method to study chronic lymphocytic leukemia, we prioritized several network TFs amenable to pharmacological perturbation and show that compounds targeting these TFs show comparable efficacy in CLL cell lines to FDA-approved therapies. The construction of transcriptional regulatory network (TRN) models can predict the interactions between individual TFs and predict critical TFs for development or disease.

systems biology↗