A cross-scale physical framework for transcription-associated CPEB4 microexon susceptibility and crowding-enhanced isoform self-association: toward a biophysical mechanism of idiopathic autism
Journal
Physical Biology
ISSN
1478-3967
Publisher
IOP Publishing
Date Issued
2026
Author(s)
Alvarado, Ysaías J.
Cardozo-Urdaneta, Arlene
Vivas, Alejandro
Lossada, Carla
Mendez, Aníbal
Portillo, Edgar
Troconis, María Elena
Delgado, Ariana
Quiroz, Yasmir
Mora, Marylu
Pérez-Castillo, Yunierkis
Vera-Villalobos, Joan
Paz, Julio de la
González-Paz, Lenin
Type
text::journal::journal article
Abstract
Co-transcriptional splicing and protein self-assembly are governed by coupled kinetic and thermodynamic constraints, such that modest changes in exon processing can propagate into substantial shifts in isoform-dependent mesoscale behavior. Here, we develop a cross-scale physical framework to examine whether transcription-associated kinetic pressure could differentially bias CPEB4 microexon selection and thereby reshape downstream isoform behavior. Using a simplified transcriptional kinetic model, we define an acetylation-associated high-throughput regime as a coarse-grained proxy for reduced time available for co-transcriptional exon recognition. Comparative sequence and structural analyses identify microexon 4 (me4) as less robust than microexon 3 (me3), with weaker cis-regulatory support and lower thermodynamic stability, consistent with greater susceptibility to omission under kinetically constrained conditions. A reduced probabilistic splicing framework accordingly predicts a directional bias against me4, superimposed on a basal transcript landscape in which the full-length isoform remains present. As a complementary downstream analysis, scaled-particle-theory calculations indicate that representative Δ4-enriched scenarios thermodynamically favor homotypic self-association under macromolecular crowding, suggesting a plausible physical amplification route for modest splicing bias. Orthogonal measurements in a yeast perturbation system identify oxidative and spectroscopic signatures compatible with strong butyrate-associated physicochemical stress, but these are interpreted as perturbation readouts rather than direct measurements of neuronal histone acetylation or splicing. Together, these results define a testable cross-scale framework linking transcription-associated kinetic constraints, directional microexon susceptibility, and crowding-dependent remodeling of the CPEB4 isoform assembly landscape. © the authors ©2026 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved. This article is available under the terms of the IOP-Standard License.
License
Acceso Restringido
How to cite
Alvarado, Y. J., Cardozo-Urdaneta, A., Vivas, A., Lossada, C., Mendez, A., Portillo, E., Troconis, M. E., Delgado, A., Quiroz, Y., Mora, M., Marrero-Ponce, Y., Martinez-Rios, F., Pérez-Castillo, Y., Vera-Villalobos, J., de la Paz, J., & González-Paz, L. (2026). A cross-scale physical framework for transcription-associated CPEB4 microexon susceptibility and crowding-enhanced isoform self-association: toward a biophysical mechanism of idiopathic autism. Physical Biology, 23(4), 046002. https://doi.org/10.1088/1478-3975/ae8d70