Biology subjects

Liu, P.-P.

Publications and source records attributed to Liu, P.-P..

6 recordsLinked to original sources

bioRxiv2026

Optogenetic Control of cAMP Levels and HCN Channels: Implications in Cardiac Physiology and Parkinsons Disease

Cyclic adenosine monophosphate (cAMP) is a second messenger that regulates various cellular processes, including the activity of hyperpolarization-activated channels (HCN), which are implicated in cardiac physiology and neurodegenerative diseases such as Parkinsons disease (PD). In this study, we used a photoactivated adenylyl cyclase (PAC) S27A mutant to optogenetically control intracellular cAMP levels. We demonstrated that light-induced elevation of cAMP activated HCN4 channels, leading to increased beating rates in cardiomyocytes. Unilateral expression of PAC(S27A) in the substantia nigra pars compacta of mice induced rotation behavior upon light stimulation, which could be attenuated by HCN inhibitors. Furthermore, PAC(S27A) activation partially recovered motor deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, accompanied by increased HCN2 channel expression in ipsilateral basal ganglia. Our findings highlight the potential of using optogenetics to modulate cAMP and HCN channel activity for the treatment of cardiac and neurological disorders.

cell biology↗

bioRxiv2026

Methodologies for Manipulating Cardiomyocyte Physiology: In Vitro and In Vivo Perspectives

Cardiac tissue is primarily made up of cardiomyocytes, which are regulated by the autonomic nervous system. We have used and developed approaches such as patch clamping and electrical stimulation-combined calcium imaging, computer modeling, optogenetics and chemogenetics combining with video-based Short-Time Fourier transformation (STFT) method to study the physiological activities of cardiomyocytes. The action potential of cardiomyocytes was found to be synchronized with calcium signals, which can be grouped into two categories by STFT. A mathematical model was developed to simulate the changes in electrical activities within cardiomyocytes caused by energy depletion, especially for 2-deoxy-D-glucose (2DG) treatment. Optogenetic and chemogenetics tools, such as ChR2(H134R), OptoXR-{beta}2AR and hM3Dq accelerated beating, while GR, ACR1 and hM4Di inhibited cardiomyocytes beating. A video-based STFT method was developed to visualize the beating frequency during these manipulations. An in vitro co-culture method was developed to study the relationship between sympathetic neuronal firing and calcium dynamics in cardiomyocytes. In vivo, electrocardiograph (ECG) measurements showed that Clozapine N-oxide (CNO) caused heart rates increasement in cTnT-hM3Dq virus injected mouse. However, it had no impact on cTnT-hM4Di virus injected mouse. This study provides comprehensive methodologies for studying cardiomyocyte physiology and manipulating heart rates in vitro and in vivo.

cell biology↗

bioRxiv2026

Optogenetic Regulation of Mitochondrial Function to Modulate Cell Death

Cell death is a critical process involved in physiological and pathological conditions, including neurodegenerative diseases and cancer. This study explores the use of optogenetic techniques to induce cell death by employing light sensitive proteins. By manipulating mitochondrial function with light-sensitive proteins, we investigated three distinct strategies: 1) inhibiting oxidative phosphorylation through Gloeobacter rhodopsin-mediated alkalization, 2) inducing mitochondrial depolarization with reverse proton-pumping rhodopsins (RPPR) and anion-conducting channelrhodopsins, and 3) generating reactive oxygen species (ROS) using mitochondria-targeted miniSOG. Our findings highlight the potential of optogenetic approaches to induce cell death, offering promising avenues for therapeutic interventions in diseases characterized by aberrant cell survival.

cell biology↗

bioRxiv2024

Mitochondrial DNA Release and Activation of the cGAS-STING Pathway in Lethal Stx12 Knockout Mice

STX12 (syntaxin12 or syntaxin13), a member of the SNARE protein family, plays a crucial role in intracellular vesicle transport and membrane fusion. Our previous research has demonstrated that Stx12 knockout mice exhibit perinatal lethality with iron deficiency anemia. Despite its importance, the comprehensive physiological and pathological mechanism of STX12 remain largely unknown. Here, we uncover that STX12 deficiency causes the depolarization of mitochondrial membrane potential in zebrafish embryos and mouse embryonic fibroblasts. Additionally, the loss of STX12 decreases levels of mitochondrial complex subunits, accompanying mitochondrial DNA (mtDNA) release and activating cGAS-STING pathway and Type I interferon pathway in the lung tissue of Stx12-/- mice. Additionally, we have observed a substantial increase in cytokines and neutrophil infiltration within the lung tissues of Stx12 knockout mice, indicating a severe inflammation, which could be a contributing factor for Stx12-/-mortality. Various interventions have failed to rescue the lethal phenotype, suggesting that systemic effects may contribute to lethality. Further research is warranted to elucidate potential intervention strategies. Overall, our findings uncover the critical role of STX12 in maintaining mitochondrial function and mtDNA stability in pulmonary cells, and reveal that STX12 depletion results in pulmonary mtDNA release and activates mtDNA-dependent innate immunity.

molecular biology↗

bioRxiv2021

Dynamic profiling and functional interpretation of histone lysine crotonylation and lactylation during neural development

BackgroundMetabolites such as crotonyl-CoA and lactyl-CoA influence gene expression through covalently modifying histones, known as histone lysine crotonylation (Kcr) and histone lysine lactylation (Kla). However, their existence patterns, dynamic changes, biological functions, as well as associations with histone lysine acetylation (Kac) and gene expression during mammalian development remain largely unknown, which imped us from understanding the epigenetic regulations of histone lysine acylations. ResultsHistone Kcr and Kla are widely distributed and undergo global changes during neural development. By profiling genome-wide dynamics of H3K9ac, H3K9cr and H3K18la in combination with ATAC sequencing and RNA sequencing, we reveal that these histone marks cooperatively regulate chromatin state and gene expression, as well as promote transcriptome remodelling to favour cell fate transition in the developing telencephalon. Importantly, we demonstrate that global histone Kcr and Kla are not consequence of transcription and furtherly identify histone deacetylase 1-3 (HDAC1-3) as novel "erasers" of H3K18la. Taking advantage of induced differentiation system of P19 embryonal carcinoma (EC) cells, we find that a selective inhibitor of HDAC1-3, MS-275 pre-activates neural fate-related transcriptional programs via stimulating multiple histone lysine acylations simultaneously. ConclusionsOur study uncover the interplays between histone lysine acylations to regulate gene expression and the differentiation-promoting functions of histone Kcr and Kla during development, and provide evidence that multiple histone lysine actlations synchronously alternate to orchestrate transcriptome responding under HDACs inhibition.

developmental biology↗

bioRxiv2020

Histone lysine crotonylation regulates cell-fate determination of neural stem/progenitor cells by activating bivalent promoters

Histone lysine crotonylation (Kcr), an evolutionarily conserved and widely expressed non-acetyl short-chain lysine acylation, plays important roles in transcriptional regulation and disease development. However, its genome-wide distribution, correlation with gene expression, and dynamic changes during developmental processes are largely unknown. In this study, we find that histone Kcr is mainly distributed in active promoters, has a ge-nome-wide positive correlation with transcriptional activity, and regulates transcription of genes participating in metabolism and proliferation. Moreover, elevated histone Kcr activates bivalent promoters to stimulate gene expression in neural stem/progenitor cells (NSPCs), through increasing chromatin openness and recruitment of RNA polymerase II (Pol II). Functionally, these activated genes remodel transcriptome and promote neuronal differentiation. Author summaryOverall, histone Kcr marks active promoters with high gene expression and modifies the local chromatin environment to allow gene activation, which influences neuronal cell fate. It may represent a unique active histone mark involved in neural developmental regulation.

cell biology↗