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Publications (27)
Residing at the top of the hematopoietic hierarchy, long-term hematopoietic stem cells (HSCs) are capable of self-renewal and sustained blood cell regeneration. Over the past decades, single-cell and clonal analyses have revealed substantial functional and molecular heterogeneity within this compartment, challenging the notion that self-renewal is...
Alternative splicing of pre-mRNA is a fundamental step in human gene regulation and aberrant slic-ing is tightly linked to diseases including cancer. Various splicing events, such as alternative exon (AE) choice and intron retention (IR), are controlled by a common molecular machinery, the spliceosome. However, it remains elusive how the regulation...
TGFβ-signaling regulates cancer progression by controlling cell division, migration, and death. These outcomes are mediated by gene expression changes, but the mechanisms of decision-making toward specific fates remain unclear. Here, we combine SMAD transcription factor imaging, genome-wide RNA sequencing, and morphological assays to quantitatively...
RNA splicing enables the functional adaptation of cells to changing contexts. Impaired splicing has been associated with diseases, including retinitis pigmentosa, but the underlying molecular mechanisms and cellular responses remain poorly understood. In this work, we report that deficiency of ubiquitin-specific protease 39 (USP39) in human cell li...
TGFβ-signaling regulates cancer progression by controlling cell division, migration and death. These outcomes are mediated by gene expression changes, but the mechanisms of decision making towards specific fates remain unclear. Here, we combine SMAD transcription factor imaging, genome-wide RNA sequencing and morphological assays to quantitatively...
Alternative splicing is an important step in eukaryotic mRNA pre-processing which increases the complexity of gene expression programs, but is frequently altered in disease. Previous work on the regulation of alternative splicing has demonstrated that splicing is controlled by RNA-binding proteins (RBPs) and by epigenetic DNA/histone modifications...
We interrogated the functional potency of individual HSCs and their paired progeny using serial single cell transplantations and mathematical modeling. Primary transplants consisted of injection of 365 single LT-HSCs (LSK, CD34-, ESLAM) into individual recipient mice (35% engraftment with >0.1% donor chimerism). A mathematical fit of this data reve...
Hematopoietic stem cells (HSCs) are the ultimate source of a large variety of mature blood and immune cells.
While the potential of HSCs has been well studied by perturbative transplantation assays, their properties and differentiation pathways remain poorly defined in physiological hematopoiesis.
Here, we chart native lineage pathways emanating fr...
Eukaryotic circadian clocks are based on self-sustaining, cell-autonomous oscillatory feedback loops that can synchronize with the environment via recurrent stimuli (zeitgebers) such as light. The components of biological clocks and their network interactions are becoming increasingly known, calling for a quantitative understanding of their role fo...
Hematopoietic stem cells (HSCs) produce highly diverse cell lineages. Here, we chart native lineage pathways emanating from HSCs and define their physiological regulation by computationally integrating experimental approaches for fate mapping, mitotic tracking, and single-cell RNA sequencing. We find that lineages begin to split when cells leave th...
Eukaryotic circadian clocks are based on self-sustaining, cell-autonomous oscillatory feedback loops that can synchronize with the environment via recurrent stimuli (zeitgebers) such as light. The components of biological clocks and their network interactions are becoming increasingly known, calling for a quantitative understanding of their role fo...
Hematopoietic stem cells (HSCs) produce a highly diverse array of cell lineages. To assay hematopoietic differentiation with minimal experimental perturbation, non-invasive methods for heritable labeling (1-3) or barcoding (4-7) of HSCs in vivo have recently been developed and used to study lineage fate of HSCs in physiological conditions. However,...
Hematopoiesis is a paradigm for tissue development and renewal from stem cells. Experiments show that the maintenance of hematopoietic stem cells (HSCs) relies on signals from niche cells. However, it is not known how the size of the HSC compartment is set. Competition by HSCs for niche access has been suggested, yet niche cells in the bone marrow...
Gene regulation is a complex non-equilibrium process. Here, we show that quantitating the temporal regulation of key gene states (transcriptionally inactive, active, and refractory) provides a parsimonious framework for analyzing gene regulation. Our theory makes two non-intuitive predictions. First, for transcription factors (TFs) that regulate tr...
Circadian oscillation is a typical nonlinear behaviour in nature. A sustained oscillatory rhythm is fundamental for gene expression, signal transduction and metabolism in living cells. By quantifying the interactions among the elements (or modules) of biological clocks, it is certainly helpful for us to understand how precisely the circadian clocks...
Circadian rhythm makes physiology and behaviors of organisms adapt to the day and night cycle in the environment. Recent experiment indicated a PER-TIM interval timer in Drosophila melanogaster cytoplasm. In this paper, we present a possible mathematical model for this interval timer. The characters of the model are the formation of big clusters, f...
A reaction-diffusion model is built to investigate the temporal and spatial patterns of cytoplasmic Ca2+ dynamics under the effects of Ca2+-release activated Ca2+ (CRAC) channels in T cells. Simulation results show a strong dependence of the modulation mode of Ca2+ oscillation and dynamic patterns of Ca2+ wave on the influx rate through the CRAC ch...
The cytoplasmic Ca oscillations are investigated under the effect of CRAC channels in non-excitable cells (especially in T cells). The oscillatory Ca2+ signals can be modulated as the amplitude-, frequency- and mixed amplitude-frequency modulation modes dependent on the different IP3R gating models. Bifurcation analyses show that Ca2+ signals in th...
This text contains detailed methods for the full Kai network and additional results.
(2.00 MB PDF)
Relationship between ST and subunit representations.
(0.08 MB PDF)
Expressions and descriptions for reaction flows.
(0.02 MB PDF)
Parameters in the estimation of free energies of all reaction and interaction processes in Kai network.
(0.12 MB PDF)
Dissociation constants and rate constants in Kai reaction network.
(0.20 MB PDF)
Combinational factors of the triplets in KaiC hexamer.
(0.05 MB PDF)
Dynamic node-to-node mass evolution in one complete KaiC phosphorylation cycle. The time for the trough of Y is set to be the zero circadian time. Mass evolution (contour map) in LC (left panel), LBC (right panel) and combined (middle panel) layers are shown. The color bar shown on right corresponds to the fraction of the amount of total KaiC hexam...
Author Summary
Circadian clocks are endogenous timing mechanisms that allow living organisms to coordinate their activities with daily environmental fluctuations. In cyanobacteria, almost all the genes are rhythmically expressed with the same ∼24 h period yet exhibit a variety of phase relationships and waveforms. Remarkably, the core pacemaker tic...
A mathematical model is proposed to illustrate the activation of STIM1 (stromal interaction molecule 1) protein, the assembly and activation of calcium-release activated calcium (CRAC) channels in T cells. In combination with De Young-Keizer-Li-Rinzel model, we successfully reproduce a sustained Ca(2+) oscillation in cytoplasm. Our results reveal t...
