Published in the prestigious journal Cell Metabolism, this research challenges the traditional understanding of genetic influence by revealing a dynamic interplay between nutrition and genetics that modulates the liver’s gene activity throughout the day. The implications are profound, suggesting that how and when our genes switch on and off in response to diet may vary greatly from person to person, potentially influencing susceptibility to obesity-related diseases and opening new avenues for personalized medicine strategies such as chronotherapy — the alignment of medical treatment schedules with the body’s natural biological rhythms.

Central to this investigation was the question that pervades both clinical and public health concerns: why do some individuals accumulate weight or develop liver complications more readily than others, despite consuming similar diets? Dr. Dongyin Guan, who spearheaded the study and serves as assistant professor of medicine with specializations in endocrinology and molecular biology at Baylor, highlights that the answer lies in the intricate relationship between one’s genetic blueprint and their nutritional environment. His team identified that specific genetic variants modulate the timing and intensity of gene activation in the liver in response to food intake, effectively dictating temporal windows during which fat metabolism genes exhibit rhythmic activity.

The study employed an integrative approach, analyzing human liver samples alongside genetically distinct mouse strains. This dual-species scrutiny allowed the team to observe how hepatic genes oscillate on a diurnal schedule and how these oscillations shift when dietary composition changes, particularly with exposure to a high-fat diet. In mice subjected to lipid-rich nutrition, gene activity rhythms did not uniformly blunt or enhance; instead, certain genes maintained their cycling, others abruptly lost their rhythmicity, and a subset even acquired new oscillatory behavior. This nuanced response underscores the individualized nature of metabolic regulation and how dietary inputs perturb normal gene expression patterns in genetically dependent ways.

Going beyond traditional gene expression profiling, the researchers delved into the three-dimensional architecture of the genome to unravel mechanisms of temporal gene regulation. They mapped how distant regulatory elements known as enhancers physically contact gene promoters at specific times of day, facilitating or dampening gene transcription in a rhythmic fashion. Strikingly, these enhancer-promoter interactions were governed by both genetic variation and nutritional state, accounting for over 80% of their daily rhythmicity. This highlights an intricate genomic choreography where the spatial folding of DNA is modulated by environmental and inherited factors to sculpt time-of-day-specific gene expression landscapes.

One of the most exciting revelations from the study was the identification of ESRRγ (Estrogen Related Receptor Gamma) as a potent regulator of these diurnal enhancer-promoter dynamics. Not traditionally categorized within the family of canonical circadian clock genes, ESRRγ emerged as a ‘noncanonical’ clock regulator critical to maintaining rhythmic gene interactions related to fat metabolism in the liver. Genetic deletion of ESRRγ in mice resulted in the loss of these rhythmic chromatin contacts and subsequent impairments in hepatic lipid processing, firmly establishing ESRRγ as a key player linking genetic architecture to metabolic timing.

Observations of fat droplet size fluctuations in the liver further corroborated the temporal dimension of fat metabolism delineated by ESRRγ activity. In genetically distinct mouse models, only those possessing functional ESRRγ exhibited significant diurnal variations in hepatic fat storage, emphasizing that individual genotypes not only influence how fats are metabolized but also when this metabolic processing peaks during the day. These findings challenge the prevailing one-size-fits-all recommendation concerning diet and emphasize the significance of considering genetic background when evaluating metabolic health and disease risk.

While this study concentrated on liver metabolism and lipid dynamics, its broader implications suggest that similar genetic-nutrition circadian interactions may operate in other organs and influence a wide spectrum of diseases. The researchers posit that deciphering the time-dependent gene regulatory networks shaped by both inherent genetic diversity and environmental factors could revolutionize personalized medicine. By tailoring meal timing, medication schedules, and therapeutic interventions to the patient’s genetic and circadian profile, healthcare can become more effective, minimizing side effects and maximizing efficacy through synchronized biological engagement.

Moreover, these insights add a vital piece to the emerging puzzle of how lifestyle factors intertwine with genetic predisposition to orchestrate complex diseases like obesity, diabetes, and nonalcoholic fatty liver disease. Recognizing the temporal modulation of gene-environment interactions elevates our understanding of metabolic regulation beyond static snapshots, portraying it as a dynamic, temporally coordinated process susceptible to precise modulation. It opens a promising field where genetic screening combined with chronobiology could guide nutrition and clinical strategies with unprecedented precision.

This work stands as a testament to the power of multidisciplinary research combining genomics, chronobiology, molecular biology, and nutritional science. By integrating high-resolution gene expression data with sophisticated 3D chromatin interaction maps, the Baylor-led team has provided a roadmap for future investigations into the molecular underpinnings of circadian metabolic control. As this field evolves, it may spur innovative approaches to manage metabolic disorders by exploiting the inherent rhythm of gene regulatory networks coupled with an individual’s genetic landscape.

Future research directions indicated by this study include exploring the extent to which other metabolic pathways, immune responses, or neurological processes are governed by similar enhancer-promoter rhythmicity influenced by genetic and dietary factors. Additionally, extending this work to diverse human populations with varying genetic backgrounds and dietary habits could help pinpoint the most impactful gene variants for targeted therapeutic intervention. Ultimately, these endeavors could lead to the development of personalized lifestyle and medical regimens designed to harmonize with both our genome and our body’s internal clock.

In conclusion, this pioneering study from Baylor College of Medicine enriches our comprehension of how everyday factors like diet interact with the intricate machinery of our genes to regulate liver metabolism in a time-dependent manner. It challenges prior conceptions of static genetic function by unveiling the fluid and conditional nature of gene activity rhythms, shaped by a dynamic interface between our environment and genotype. Such knowledge not only advances fundamental science but also paves the way toward a future where chronotherapy and individualized nutritional guidance become mainstays of effective disease prevention and management.

Subject of Research: Animals

Article Title: Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism

News Publication Date: 25-Aug-2025

Web References:

• Cell Metabolism Article
• DOI link

References: The study referenced multiple NIH grants as well as funding from CPRIT, V Foundation, USDA/ARS, Pew Foundation, and other institutions.

Keywords: Health and medicine, Clinical medicine, Diseases and disorders, Human health, Life sciences, Cell biology, Neuroscience, Physiology

The team, led by Fu, Okawa, and Vinaikosol, focused on the effects of shaking culture, a prevalent mechanical stimulation technique, on the circadian clock machinery inherent in iPSCs undergoing osteogenic differentiation. Circadian rhythms, the approximately 24-hour cycles governing physiological processes, have previously been shown to influence cellular functions ranging from metabolism to cell division. However, their role and modulation during stem cell fate determination have remained enigmatic and underexplored.

Central to the study is the TEAD-Fbxl3-CRY axis, a molecular cascade that integrates mechanical cues with circadian regulation. TEAD transcription factors, known for their pivotal role in controlling gene expression linked to cell proliferation and differentiation, appear to orchestrate the downstream activity of Fbxl3, an F-box protein that targets circadian repressors such as CRY for ubiquitination and proteasomal degradation. This axis acts as an essential intermediary transforming mechanical forces from the shaking culture environment into tangible alterations in the molecular circadian clock.

Experimental evidence from carefully controlled shaking culture systems demonstrated a marked attenuation of circadian amplitude in iPSCs progressing toward osteoblast-like phenotypes. This attenuation manifests as dampened oscillations in core clock genes, particularly cryptochromes (CRYs), which are fundamental repressors within the circadian feedback loop. The dampened rhythms suggest that continuous mechanical stimulation disrupts the normal temporal signaling required for finely tuned gene expression during differentiation.

The importance of this finding lies in the intricate interplay between circadian biology and stem cell fate decisions. Osteogenic differentiation is a tightly regulated process involving sequential activation and repression of lineage-specific genes. Disruption of circadian rhythms may lead to aberrant timing in gene expression, potentially influencing the functionality and quality of differentiated bone cells. This concept challenges existing paradigms that often overlook temporal regulation in the differentiation milieu.

Moreover, the identification of the TEAD-Fbxl3-CRY axis as a key mediator provides a molecular handle to manipulate circadian dynamics experimentally. By modulating TEAD activity or Fbxl3 expression, it may be possible to rescue or fine-tune circadian oscillations even under mechanical stress. Such interventions could enhance the robustness and predictability of stem cell-derived osteogenic therapies, which are essential for skeletal repair and regeneration.

Mechanotransduction, the process through which cells convert mechanical stimuli into biochemical signals, has been increasingly recognized as a critical regulator in stem cell biology. Shaking culture represents a form of dynamic mechanical stimulation that mimics physiological movements inherent to bone tissue. Insights from this study suggest that mechanotransduction not only influences cytoskeletal organization and gene expression but extends its regulatory reach to the cellular timekeeping mechanisms.

Interestingly, this attenuation of circadian rhythms under shaking conditions contrasts with previous observations in static cultures, highlighting the complexity of in vitro differentiation systems. These findings underscore the necessity to consider culture conditions as active variables that profoundly affect cellular phenotypes and molecular states. It also raises questions about how in vivo mechanical forces influence circadian biology during bone development and remodeling.

The researchers employed sophisticated techniques such as real-time bioluminescence reporting of circadian gene activity, quantitative PCR, and protein interaction assays to delineate the molecular underpinnings of this phenomenon. The convergence of these methodologies enabled a comprehensive characterization of the TEAD-Fbxl3-CRY pathway’s involvement and established a direct causative link between mechanical cues and circadian modulation.

Looking ahead, this work paves the way for designing biomimetic culture systems that could harness or circumvent mechanical influences on circadian regulation, tailoring differentiation protocols with temporal precision. Such approaches could optimize the generation of bone tissue constructs with enhanced functionality and integration potential upon transplantation.

Beyond osteogenesis, the broader implications of this research hint at an overarching principle wherein mechanical environments serve as temporal “zeitgebers” (time-givers), synchronizing or disrupting circadian clocks across diverse stem cell types and tissues. Future studies may explore whether similar mechanisms operate in other lineage pathways and how these dynamics affect aging, disease susceptibility, and tissue homeostasis.

This revelation of shaking culture’s influence on circadian rhythms also resonates with an evolving appreciation of chronobiology in regenerative medicine. By aligning cell therapy strategies with circadian principles, clinicians and researchers may improve therapeutic efficacy, minimize adverse effects, and promote long-term tissue health.

In conclusion, the identification of the TEAD-Fbxl3-CRY axis as a bridge between mechanical stimuli and circadian attenuation in iPSC-derived osteogenic cells represents a significant advance in stem cell biology. It challenges us to rethink the temporal dimension within differentiation paradigms, emphasizing that the “when” can be just as critical as the “what” and “how” in guiding cell fate and function. As this line of research progresses, it promises to unlock new strategies for better harnessing the potential of stem cells in medicine, engineering, and understanding fundamental biological rhythms.

Subject of Research:
Article Title:
Article References: Fu, Y., Okawa, H., Vinaikosol, N. et al. Shaking culture attenuates circadian rhythms in induced pluripotent stem cells during osteogenic differentiation through the TEAD-Fbxl3-CRY axis. Cell Death Discov. 11, 252 (2025). https://doi.org/10.1038/s41420-025-02533-6
Image Credits: AI Generated
DOI: https://doi.org/10.1038/s41420-025-02533-6