Biology subjects

Carrillo, J. A.

Publications and source records attributed to Carrillo, J. A..

6 recordsLinked to original sources

bioRxiv2025

Epigenetic control of microglial developmental milestones from proliferative progenitors to efficient phagocytes

Early immune perturbations increase the risk of neurodegenerative and neurodevelopmental disorders, yet the mechanisms underlying the maturation of microglia, the resident immune cells of the brain parenchyma, remain poorly defined. Specifically, how proliferation, morphological differentiation, and phagocytosis are coordinated among microglia progenitors as they colonize the embryonic brain remains unclear. Here, we combined mathematical modeling with spatiotemporal analyses of the murine hippocampus and cerebellum from postnatal day 2 (P2) to P60 to reconstruct the trajectory of microglial development. We identified a proliferative-to-quiescent (P/Q) switch around P3/P4 that preceded the acquisition of morphological complexity and efficient phagocytosis and was accompanied by coordinated shifts in cell-cycle dynamics and metabolic state. Strikingly, this P/Q switch was recapitulated in repopulation contexts in mice and in the human fetal brain, where later stages displayed enhanced phagocytic function coupled to reduced proliferation. Perturbing the proliferative phase through pharmacological or genetic disruption of CSF1R signaling impaired subsequent microglial complexity and phagocytosis efficiency, revealing an unexpected reliance of phagocytosis on proliferation-driven colonization. Finally, we show that microglia stepwise maturation during development is associated with chromatin remodeling and driven by the epigenetic regulator Ikaros. Together, these findings uncover the sequential milestones of microglial development, revealing a potential period of early vulnerability and establishing an unexpected linkage between proliferation and phagocytosis essential to understanding how these processes are coordinated in neurodegenerative disorders.

neuroscience↗

bioRxiv2025

Epigenetic Programming of Estrogen Receptor in Adipose Tissue by High Fat Diet Regulates Obesity-Induced Inflammation

Adipose inflammation plays a key role in obesity-induced metabolic abnormalities. Epigenetic regulation, including DNA methylation, is a molecular link between environmental factors and complex diseases. Here we found that high fat diet (HFD) feeding induced a dynamic change of DNA methylome in mouse white adipose tissue (WAT) analyzed by reduced representative bisulfite sequencing. Interestingly, DNA methylation at the promoter of estrogen receptor (Esr1) was significantly increased by HFD, concomitant with a down-regulation of Esr1 expression. HFD feeding in mice increased the expression of DNA methyltransferase 1 (Dnmt1) and Dnmt3a, and binding of DNMT1 and DNMT3a to Esr1 promoter in WAT. Mice with adipocyte-specific Dnmt1 deficiency displayed increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity upon HFD challenge; while mice with adipocyte-specific Dnmt3a deficiency showed a mild metabolic phenotype. Using a modified CRISPR/RNA-guided system to specifically target DNA methylation at the Esr1 promoter in WAT, we found that reducing DNA methylation at Esr1 promoter increased Esr1 expression, decreased adipose inflammation and improved insulin sensitivity in HFD-challenged mice. Our study demonstrates that DNA methylation at Esr1 promoter plays an important role in regulating adipose inflammation, which may contribute to obesity-induced insulin resistance.

physiology↗

bioRxiv2025

Collective Transitions from Orbiting to Matrix Invasion in 3D Multicellular Spheroids

Coordinated cell rotation along a curved matrix interface can sculpt epithelial tissues into spherical morphologies. Subsequently, radially-oriented invasion of multicellular strands or branches can occur by local remodeling of the confining matrix. These symmetry-breaking transitions emerge from the dynamic reciprocity between cells and matrix, but remain poorly understood. Here, we show that epithelial cell spheroids collectively transition from circumferential orbiting to radial invasion via bi-directional interactions with the surrounding matrix curvature. Initially, spheroids exhibit an ellipsoidal shape but become rounded as orbiting occurs. However, cells gradually reorient from coordinated rotation towards outward strand invasion due to the accumulation of contractile tractions at discrete sites. Remarkably, the initial ellipsoid morphology predicts subsequent invasion of 2-4 strands roughly aligned with the major axis. We then perturb collective migration using osmotic pressure, showing that orbiting can be arrested and invasion can be reversed. We also investigate coordinated orbiting in "mosaic" spheroids, showing a small fraction of "leader" cells with weakened cell-cell adhesions can impede collective orbiting but still invade into the matrix. Finally, we establish a minimal self-propelled particle model to elucidate how collective orbiting is mediated by the crosstalk of cell-cell and cell-matrix adhesion along a curved boundary. Altogether, this work elucidates how tissue morphogenesis is governed by the interplay of collective behaviors and the local curvature of the cell-matrix, with relevance for embryonic development and tumor progression.

biophysics↗

bioRxiv2024

A new paradigm considering multicellular adhesion, repulsion and attraction represent diverse cellular tile patterns

Cell sorting by differential adhesion is one of the basic mechanisms explaining spatial organization of neurons in early stage brain development of fruit flies. The columnar arrangements of neurons determine the large scale patterns in the fly visual center. Experimental studies indicate that hexagonal configurations regularly appear while tetragonal configurations can be induced in mutants. Mathematical models based on macroscopic approximations of agent based models (ARA models) are shown to produce a similar behavior changing from hexagonal to tetragonal steady configurations when medium range repulsion and longer-range attraction between individuals is incorporated in previous successful models for cell sorting based on adhesion and volume constraints. We analyse the angular configurations of these patterns based on angle summary statistics and compare between experimental data and parameter fitted ARA models showing that intermediate patterns between hexagonal and tetragonal configuration are common in experimental data as well as in our ARA mathematical model. Our studies indicate an overall qualitative agreement of ARA models in tile patterning and pave the way for their quantitative studies. 2010 MSC92C17, 92C37, 35Q92

developmental biology↗

bioRxiv2019

DNA methylation, microRNA expression profiles and their relationships with transcriptome in grass-fed and grain-fed Angus Cattle rumen tissue

Rumen is a critical organ for supplying nutrients for the growth and production of bovine, which might function differently under grass-fed and grain-fed regimens considering the association of gene expression, DNA methylation, and microRNA expression. The objective of this study was to explore the potential mechanism influencing rumen function of grass-fed and grain-fed animals. Methylated DNA binding domain sequencing (MBD-Seq) and microRNA-Seq were respectively utilized to detect the DNA methylation and microRNA expression in rumen tissue of grass-fed and grain-fed Angus cattle. Integration analysis revealed that the expression of the differentially expressed genes ADAMTS3 and ENPP3 was correlated with the methylation abundance of the corresponding DMRs inside these two genes, and these two genes were reported to be respectively involved in biosynthesis and regulation of glycosyltransferase activity; the differentially expressed microRNA bta-mir-122 was predicted to possibly target the differentially expressed genes OCLN and RBM47, potentially affecting the rumen function; the microRNA bta-mir-655 was exclusively detected in grain-fed group; its targets were involved in the significantly enriched insulin and TGF-beta signaling pathways, which might worked together to regulate the function of rumen, resulting in different characteristics between grass-fed and grain-fed cattle. Collectively, our results provided insights into understanding the mechanisms determining rumen function and unraveled the biological basis underlying the economic traits to improve the productivity of animals.

genomics↗

bioRxiv2018

Collective search with finite perception: transient dynamics and search efficiency

Motile organisms often use finite spatial perception of their surroundings to navigate and search their habitats. Yet standard models of search are usually based on purely local sensory information. To model how a finite perceptual horizon affects ecological search, we propose a framework for optimal navigation that combines concepts from random walks and optimal control theory. We show that, while local strategies are optimal on asymptotically long and short search times, finite perception yields faster convergence and increased search efficiency over transient time scales relevant in biological systems. The benefit of the finite horizon can be maintained by the searchers tuning their response sensitivity to the length scale of the stimulant in the environment, and is enhanced when the agents interact as a result of increased consensus within subpopulations. Our framework sheds light on the role of spatial perception and transients in search movement and collective sensing of the environment.

biophysics↗