Biology subjects

Xiao, J. Y.

Publications and source records attributed to Xiao, J. Y..

5 recordsLinked to original sources

bioRxiv2026

The functional diversification of somatosensory neuron repertoires across Mammalia

The striking diversity of mammalian body forms and surfaces, lifestyles, and habitats prompts the question of how each species' somatosensory neuron repertoire accommodates such diversity. The visual and olfactory systems diversify by gaining and losing sensor/receptor genes and corresponding sensory cell types. Using multiomic single-cell analysis of dorsal root ganglia neurons from thirteen different mammalian species and cross-species functional studies enabled by cell-type-specific enhancer viruses, we show that mammals instead assemble species-specific, functionally distinct somatosensory neuron repertoires from a conserved set of neuron types (orthotypes). Repertoire diversification takes multiple forms: orthotype abundance scales with variable bodily traits like hair follicle density, facilitating relevant behaviors; sensor/receptor expression is shuffled across species, such that orthotypes can detect different stimuli in different species; and orthotypes split into functionally distinct, species-specific subtypes (paratypes). Thus, unlike other sensory systems, the mammalian somatosensory system diversifies through multifarious changes to conserved orthotypes, enabling adaptation to diverse habitats, lifestyles, and body forms.

neuroscience↗

bioRxiv2025

Division Asymmetry Drives Cell Size Variability in Budding Yeast

Cell size variability within proliferating populations reflects the interdependent regulation of cell growth and division as well as intrinsically stochastic effects. In budding yeast, the G1/S transition exerts strong size control in daughter cells, which manifests as the inverse correlation between how big a cell is when it is born and how much it grows in G1. However, mutations affecting this size control checkpoint only modestly influence population-wide size variability, often altering the coefficient of variation (CV) only by [~]10%. To resolve this paradox, we combine computational modeling and live-cell imaging to identify the principal determinants of cell size variability. Using an experimentally validated stochastic model of the yeast cell cycle, we perform parameter sensitivity analysis and find that division asymmetry between mothers and daughters is the dominant driver of CV, outweighing the effects of G1/S size control. Experimental measurements across genetic perturbations and growth conditions confirm a strong correlation between mother-daughter size asymmetry and population CV. These findings reconcile previous observations and show how asymmetric division operates in concert with G1/S size control to govern cell size heterogeneity.

cell biology↗

bioRxiv2025

A Fkh1/2 binding site array in the WHI5 promoter drives sub-scaling transcription

Cells typically regulate their size within a relatively tight range by coupling growth to the cell division cycle using a dedicated set of molecular mechanisms. In budding yeast, cells are born with a similar amount of the G1/S inhibitor protein Whi5 that is then diluted by growth throughout G1. As cells grow, Whi5 concentration decreases and cells become more likely to enter the cell cycle. Cells are born in G1 with similar amounts of Whi5 because of the size-independent (sub-scaling) expression of WHI5 mRNA during S/G2/M phases and the equal partitioning of Whi5 protein at division. While the latter is known to be achieved by association with chromatin before anaphase, the mechanism for the former is poorly understood. Through systematic mutations of the WHI5 promoter, we discovered that WHI5s core promoter region located -126 to -75 base pairs upstream of the start codon is responsible for sub-scaling expression. This sequence contains a repeating array of binding sites for the transcription factors Fkh1 and Fkh2. Mutation of any of these sites, deletion of either FKH1 or FKH2, or preventing Fkh1 or Fkh2 dimerization weakens the sub-scaling of WHI5 transcription. Taken together with structural predictions and a mathematical model of cooperative Fkh-DNA binding, we conclude that WHI5s sub-scaling transcription is regulated by a Fkh1/2 heteropolymer binding an array of sites in its core promoter.

cell biology↗

bioRxiv2023

Whi5 hypo- and hyper- phosphorylation dynamics control cell cycle entry and progression

Progression through the cell cycle depends on the phosphorylation of key substrates by cyclin-dependent kinases. In budding yeast, these substrates include the transcriptional inhibitor Whi5 that regulates the G1/S transition. In early G1 phase, Whi5 is hypo-phosphorylated and inhibits the SBF complex that promotes transcription of the cyclins CLN1 and CLN2. In late-G1, Whi5 is rapidly hyper-phosphorylated by Cln1,2 in complex with the cyclin-dependent kinase Cdk1. This hyper-phosphorylation inactivates Whi5 and excludes it from the nucleus. Here, we set out to determine the molecular mechanisms responsible for Whi5s multi-site phosphorylation and how they regulate the cell cycle. To do this, we first identified the 19 Whi5 sites that are appreciably phosphorylated and then determined which of these sites are responsible for G1 hypo-phosphorylation. Mutation of 7 sites removed G1 hypo-phosphorylation, increased cell size, and delayed the G1/S transition. Moreover, the rapidity of Whi5 hyper-phosphorylation in late G1 depends on priming sites that dock the Cks1 subunit of Cln1,2-Cdk1 complexes. Hyper-phosphorylation is crucial for Whi5 nuclear export, normal cell size, full expression of SBF target genes, and timely progression through both the G1/S transition and S/G2/M phases. Thus, our work shows how Whi5 phosphorylation regulates the G1/S transition and how it is required for timely progression through S/G2/M phases and not only G1 as previously thought.

cell biology↗

bioRxiv2020

How subtle changes in 3D structure can create large changes in transcription

Animal genomes are organized into topologically associated domains (TADs), which exhibit more intra-domain than inter-domain contact. However, the absolute difference in contact is usually no more than twofold, even though disruptions to TAD boundaries can change gene expression by 8-10 fold. Existing models fail to explain this superlinear transcriptional response to changes in genomic contact. Here, we propose a futile cycle model where an enzyme stimulated by association with its products can exhibit bistability and hysteresis, allowing a small increase in enhancer-promoter contact to produce a large change in expression without obvious correlation between E-P contact and promoter activity. Through mathematical analysis and stochastic simulation, we show that this system can create an illusion of enhancer-promoter specificity and explain the importance of weak TAD boundaries. It also offers a mechanism to reconcile recent global cohesin loop disruption and TAD boundary deletion experiments. We discuss the model in the context of these recent controversial experiments. Together, these analyses advance our interpretation and understanding of cis-regulatory contacts in controlling gene expression, and suggest new experimental directions.

biophysics↗