Biology subjects

Liu, A. C.

Publications and source records attributed to Liu, A. C..

8 recordsLinked to original sources

bioRxiv2026

Divergent signaling profiles in mTOR gain-of-function Smith-Kingsmore syndrome (SKS) and TSC2 deficiency

Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder caused by gain-of-function mutations in MTOR, yet whether these mutations phenocopy TSC2 loss or establish a distinct signaling state remains unclear. Using quantitative proteomics, phosphoproteomics, and transcriptomics in isogenic cell models of SKS (MTOR{Delta}4aa), TSC2 loss (TSC2-/-), and wild-type controls under glucose depletion and refeeding, we find that MTOR{Delta}4aa and TSC2-/- cells occupy fundamentally distinct regulatory states. TSC2-/- cells exhibit broad anabolic remodeling and a transcriptional program dominated by NF-{kappa}B- and STAT-driven inflammatory responses. MTOR{Delta}4aa cells instead display enrichment of nuclear and RNA processing programs, E2F/MYC-driven transcription, and a constrained proteomic dynamic range across nutrient states. Phosphoproteomic analysis of MTOR{Delta}4aa reveals rerouting of nutrient-responsive signaling toward MAPK/ERK- and Ca2+/CaMK-dependent pathways with limited canonical mTORC1/S6K1 engagement. These findings establish SKS as a signaling rewiring disorder distinct from classical mTORC1 hyperactivation, with implications for therapeutic targeting.

molecular biology↗

bioRxiv2023

Sleep Disruption in a Mouse Model of Chronic Traumatic Brain Injury

Chronic sleep/wake disturbances are strongly associated with traumatic brain injury (TBI) in patients and are being increasingly recognized. However, the underlying mechanisms are largely understudied and there is an urgent need for animal models of lifelong sleep/wake disturbances. The objective of this study was to develop a chronic TBI rodent model and investigate the lifelong chronic effect of TBI on sleep/wake behavior. We performed repetitive midline fluid percussion injury (rmFPI) in four months old mice and monitored their sleep/wake behavior using the non-invasive PiezoSleep system. The sleep/wake states were recorded before injury (baseline) and then monthly thereafter. We found that TBI mice displayed a significant decrease in sleep duration in both the light and dark phases, beginning at three months post-TBI and continuing throughout the study. Consistent with the sleep phenotype, these TBI mice showed circadian locomotor activity phenotypes and exhibited reduced anxiety-like behavior. TBI mice also gained less weight, and had less lean mass and total body water content, compared to sham controls. Furthermore, TBI mice showed extensive brain tissue loss and increased GFAP and IBA1 levels in the hypothalamus and the vicinity of the injury, indicative of chronic neuropathology. In summary, our study identified a critical time window of TBI pathology and associated circadian and sleep/wake phenotypes. Future studies should leverage this mouse model to investigate the molecular mechanisms underlying the chronic sleep/wake phenotypes following TBI early in life.

neuroscience↗

bioRxiv2022

Defining the age-dependent and tissue-specific circadian transcriptome in male mice

Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence supports age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profiled the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in 3 age groups. We found age-dependent and tissue-specific clock output changes. Aging reduced the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. Many genes gained rhythmicity in old tissues, reflecting an adaptive response. REGs were enriched for the hallmarks of aging, adding a new dimension to our understanding of aging. Differential gene expression analysis found that there were temporally distinct clusters of genes in tissue-specific manner. Increased daily gene expression variability is a common feature of aged tissues. This novel analysis extends the landscape of the understanding of aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression. HIGHLIGHTS- Rhythmically expressed genes (REGs) in Young, but not Old mice, are enriched for the aging hallmarks across all tissues. - The numbers of REGs decline across all tissues with age implicating the circadian clock in altered homeostasis. - Age- and tissue-specific differentially expressed genes (DEGs) cluster at specific times of the day. - Increase in gene expression variability over a day is a common feature of aging tissues.

genomics↗

bioRxiv2022

Experimental Design and Power Calculation in Omics Circadian Rhythmicity Detection

Circadian clocks are 24-hour endogenous oscillators in physiological and behavioral processes. Though recent transcriptomic studies have been successful in revealing the circadian rhythmicity in gene expression, the power calculation for omics circadian analysis have not been fully explored. In this paper, we develop a statistical method, namely CircaPower, to perform power calculation for circadian pattern detection. Our theoretical framework is determined by three key factors in circadian gene detection: sample size, intrinsic effect size and sampling design. Via simulations, we systematically investigate the impact of these key factors on circadian power calculation. We not only demonstrate that CircaPower is fast and accurate, but also show its underlying cosinor model is robust against variety of violations of model assumptions. In real applications, we demonstrate the performance of CircaPower using mouse pan-tissue data and human post-mortem brain data, and illustrate how to perform circadian power calculation using mouse skeleton muscle RNA-Seq pilot as case study. Our method CircaPower has been implemented in an R package, which is made publicly available on GitHub (https://github.com/circaPower/circaPower).

genomics↗

bioRxiv2021

Pyruvate kinase M1 suppresses development and progression of prostate adenocarcinoma

Most cancers, including prostate cancers, express the M2 splice isoform of pyruvate kinase (Pkm2). This isoform can promote anabolic metabolism to support cell proliferation; however, Pkm2 expression is dispensable for many cancers in vivo. Pyruvate kinase M1 (Pkm1) isoform expression is restricted to relatively few tissues and has been reported to promote growth of select tumors, but the role of PKM1 in cancer has been less studied. Pkm1 is expressed in normal prostate tissue; thus, to test how differential pyruvate kinase isoform expression affects cancer initiation and progression we generated mice harboring a conditional allele of Pkm1 and crossed this allele, as well as a Pkm2 conditional allele, to a Pten loss-driven prostate cancer model. We found that Pkm1 loss leads to Pkm2 expression and accelerates prostate cancer, while deletion of Pkm2 leads to increased Pkm1 expression and suppresses cancer. Consistent with these data, a small molecule pyruvate kinase activator that mimics a PKM1-like state suppresses progression of established prostate tumors. PKM2 expression is retained in most human prostate cancers, arguing that pharmacological PKM2 activation may be beneficial for some prostate cancer patients.

cancer biology↗

bioRxiv2021

Machine learning approaches to identify sleep genes

Genetics impacts sleep, yet, the molecular mechanisms underlying sleep regulation remain elusive. We built machine learning (ML) models to predict genes based on their similarity to known sleep genes. Using a manually curated list of 109 labeled sleep genes, we trained a prediction model on thousands of published datasets, representing circadian, immune, sleep deprivation, and many other processes. Our predictions fit with prior knowledge of sleep regulation and also identify several key genes/pathways to pursue in follow-up studies. We tested one of our findings, the NF-{kappa}B pathway, and showed that its genetic alteration affects sleep duration in mice. Our study highlights the power of ML to integrate prior knowledge and genome-wide data to study genetic regulation of sleep and other complex behaviors.

genomics↗

bioRxiv2021

Likelihood-based Tests for Detecting CircadianRhythmicity and Differential Circadian Patterns in Transcriptomic Applications

Circadian rhythmicity in transcriptomic profiles has been shown in many physiological processes, and the disruption of circadian patterns has been founded to associate with several diseases. In this paper, we developed a series of likelihood-based methods to detect (i) circadian rhythmicity (denoted as LR rhythmicity) and (ii) differential circadian patterns comparing two experimental conditions (denoted as LR diff). In terms of circadian rhythmicity detection, we demonstrated that our proposed LR rhythmicity could better control the type I error rate compared to existing methods under a wide variety of simulation settings. In terms of differential circadian patterns, we developed methods in detecting differential amplitude, differential phase, differential basal level, and differential fit, which also successfully controlled the type I error rate. In addition, we demonstrated that the proposed LR diff could achieve higher statistical power in detecting differential fit, compared to existing methods. The superior performance of LR rhythmicity and LR diff was demonstrated in two real data applications, including a brain aging data (gene expression microarray data of human postmortem brain) and a time-restricted feeding data (RNA sequencing data of human skeletal muscles). An R package for our methods is publicly available on GitHub https://github.com/diffCircadian/diffCircadian.

bioinformatics↗

bioRxiv2020

NF-κB modifies the mammalian circadian clock through interaction with the core clock protein BMAL1

In mammals, the circadian clock coordinates various cell physiological processes, including the inflammatory response. Recent studies suggested a crosstalk between these two pathways. However, the mechanism of how inflammation affects the circadian clock is not well understood. Here, we investigated the role of the proinflammatory transcription factor NF-{kappa}B in regulating clock function. Using a combination of genetic and pharmacological approaches, we show that perturbation of the canonical NF-{kappa}B subunit RELA in the U2OS cellular model altered core clock gene expression. While RELA activation shortened period length and dampened amplitude in these cells, its inhibition lengthened period length and caused amplitude phenotypes. NF-{kappa}B perturbation also altered circadian rhythms in the master suprachiasmatic nucleus (SCN) clock and locomotor activity. We show that RELA, like the clock repressor CRY1, potently repressed the transcriptional activity of BMAL1/CLOCK at the circadian E-box cis-element. Biochemical and biophysical analysis showed that RELA competes with coactivator CBP/p300 for binding to the transactivation domain of BMAL1. This mechanism is further supported by chromatin immunoprecipitation analysis showing that the binding sites of RELA, BMAL1 and CLOCK converge on the E-boxes of clock genes. Taken together, these data support a significant role for NF-{kappa}B in directly regulating circadian clock function and highlight mutual regulation between the circadian and inflammatory pathways.

molecular biology↗