Biology subjects

Teruel, M.

Publications and source records attributed to Teruel, M..

5 recordsLinked to original sources

bioRxiv2026

Parental B-MYB/FOXM1 controls mitotic E2F to determine daughter cell fate

Mitogens trigger cell-cycle entry by activating E2F at the restriction point, which is followed by B-MYB/FOXM1 activation and progression to mitosis. How mitogens control continued cycling and cell-cycle exit after the restriction point is not well-understood. By developing an E2F and B-MYB/FOXM1 dual transcriptional biosensor system, we show that S/G2 phase duration is set by timed mitogen-regulated B-MYB/FOXM1 activation, while E2F activity gradually declines before mitosis. As a striking consequence, rapid B-MYB/FOXM1 activation shortens S/G2, delivering high mitotic E2F activity to daughter cells which keeps them cycling. Delayed B-MYB/FOXM1 activation prolongs S/G2, depleting mitotic E2F which drives daughters to quiescence. When S/G2 is further prolonged, partially activated B-MYB/FOXM1 frequently reverts, triggering mitotic bypass and polyploid quiescence. Thus, B-MYB/FOXM1 governs a tri-directional (G2 restriction point) where cells commit to continued cycling through early B-MYB/FOXM1 activation; cell-cycle exit through delayed B-MYB/FOXM1 activation; or mitotic bypass by B-MYB/FOXM1 inactivation.

cell biology↗

bioRxiv2022

The circadian clock mediates daily bursts of cell differentiation by periodically restricting cell differentiation commitment

Most mammalian cells have an intrinsic circadian clock that coordinates their metabolic activity with the daily rest and wake cycle. In addition, the circadian clock is known to regulate cell differentiation, but how continuous daily oscillations of the internal clock control a much longer, multi-day differentiation process is not known. Here we simultaneously monitor the circadian clock and progression of adipocyte differentiation live in single cells. Strikingly, we find a bursting behavior in the cell population whereby individual preadipocytes commit to differentiate primarily during a 12-hour window each day corresponding to the time of rest. Daily gating of differentiation occurs because cells can irreversibly commit to differentiate within a few hours, which is faster than the rest phase and much faster than the overall multi-day differentiation process. We show that the daily bursts in differentiation are driven by a variable and slow increase in expression of PPARG, the master regulator of adipogenesis, combined with rapid, clock-driven expression of CEBPA, which is in a fast positive feedback relationship with PPARG. During each rest cycle, the increase in CEBPA causes a brief step increase in PPARG so that some cells can reach the threshold to irreversibly commit to differentiate, causing the consecutive daily bursts in cell differentiation at the population level. Our findings are broadly relevant given that most differentiating somatic cells are regulated by the circadian clock. Having a restricted time each day when differentiation occurs may open therapeutic strategies to use timed treatment relative to the clock to promote tissue regeneration. Significance StatementCells rely on a circadian clock that coordinates cellular activities with the day-night cycle. Defects in circadian clock genes dysregulate cell differentiation processes in immune, muscle, skin and fat cells. However, how a perpetual daily clock can regulate a multi-day long cell differentiation process was not understood. Here we show that the circadian clock controls a fast upregulation of the transcription factor CEBPA during each daily rest phase which in turn controls a fast irreversible step during the overall slow multi-day differentiation of fat cells, causing daily bursts of cell differentiation. Our finding opens potential therapeutic strategies to enhance tissue regeneration by timing when during the day drugs are administered.

cell biology↗

bioRxiv2020

Flattened circadian glucocorticoid oscillations cause obesity due to increased lipid turnover and lipid uptake

Chronic stressors flatten diurnal glucocorticoid oscillations, resulting in obesity, insulin resistance, and diabetes. How such flattened diurnal glucocorticoid oscillations increase fat storage is unknown. Here we investigated the consequences in mice and found that flattening of glucocorticoid oscillations results not only in body weight gain, mainly due to increases in white fat depot mass, but also leads to hyperinsulinemia and fat accumulation in brown adipose tissue. A transcriptomic analysis of white and brown adipose tissues revealed that flattened glucocorticoid oscillations cause dysregulated lipid metabolism with a prominent role of the fatty acid transporter Cd36 and insulin-driven adipocyte hypertrophy. Indeed, Cd36 knockout mice are partially protected against the adverse effects of flattened GC oscillations including body weight gain and lipid accumulation in the brown and visceral white fat depots. These results show the molecular mechanisms how flattened glucocorticoid oscillations can cause obesity and diabetes.

physiology↗

bioRxiv2020

The highly expressed lipid buffer FABP4 enforces adipocyte cell identity by driving the initial cell differentiation process

How progenitor cells can attain a distinct differentiated cell identity is a challenging problem given that critical transcription factors are often not unique to a differentiation process and the fluctuating signaling environment in which cells exist. Here we test the hypothesis that a unique differentiated cell identity can result from a core component of the differentiated state doubling up as a signaling protein that also drives differentiation. Using live single-cell imaging in the adipocyte differentiation system, we show that progenitor fat cells (preadipocytes) can only commit to terminally differentiate after upregulating FABP4, a lipid buffer that is highly enriched in mature adipocytes. Upon induction of adipogenesis, we show that after a long delay, cells first abruptly start to engage a positive feedback between CEBPA and PPARG before then engaging, after a second delay, a positive feedback between FABP4 and PPARG. These sequential positive feedbacks both need to engage in order to drive PPARG levels past the threshold for irreversible differentiation. In the last step before commitment, PPARG transcriptionally increases FABP4 expression while fatty-acid loaded FABP4 binds to and increases PPARG activity. Together, our study suggests a control principle for robust cell identity whereby a core component of the differentiated state also promotes differentiation from its own progenitor state. HIGHLIGHTSO_LIFatty-acid loaded FABP4 binds to and increases PPARG expression, thereby turning on PPARG positive feedback loops that further increase PPARG expression. C_LIO_LIFABP4 critically controls the second phase of adipogenesis between activation of the feedback loops and reaching the threshold to differentiate. C_LIO_LIOnly a small fraction ([~]10%) of the FABP4 levels typically attained in mature fat cells is needed to commit cells to the differentiated state, thus providing an explanation for why maintenance of the mature adipocyte state is so robust. C_LI

cell biology↗

bioRxiv2019

Loss of adipocyte identity through synergistic repression of PPARγ by TGF-β and mechanical stress

Adipocytes convert into myofibroblasts in a TGF-{beta}-dependent mouse model of fibrosis. The molecular steps and timing underlying this conversion are poorly understood, hindering development of antifibrotic therapies. Here we used two single-cell approaches, lineage tracing and live-cell imaging of an adipocyte marker PPAR{gamma}, to track the fate of adipocytes induced to convert by TGF-{beta}. We found that TGF-{beta} alone was not sufficient to activate the TGF-{beta} pathway and to induce myofibroblast conversion in cells with high PPAR{gamma} expression. However, robust conversion was observed when an additional PPAR{gamma}-inhibiting stimulus, mechanical stress applied by increasing adhesion area on a stiff matrix, was applied simultaneously with TGF-{beta}. We show that the PPAR{gamma} downregulation in response to increased adhesion area required both fibronectin and a sufficiently stiff extracellular matrix (ECM) and was partially mediated by Rho. Our results show for the first time the order of the molecular processes driving fat tissue fibrosis and the requirement for signal convergence for the loss of adipocyte identity.

cell biology↗