Pluralistic and stochastic gene regulation: Examples, models and consistent theory

Elisa N. Salas, Jiang Shu, Matyas F. Cserhati, Donald P. Weeks, Istvan Ladunga

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

We present a theory of pluralistic and stochastic gene regulation. To bridge the gap between empirical studies and mathematical models, we integrate pre-existing observations with our meta-analyses of the ENCODE ChIP-Seq experiments. Earlier evidence includes fluctuations in levels, location, activity, and binding of transcription factors, variable DNA motifs, and bursts in gene expression. Stochastic regulation is also indicated by frequently subdued effects of knockout mutants of regulators, their evolutionary losses/gains and massive rewiring of regulatory sites. We report wide-spread pluralistic regulation in ≈800 000 tightly co-expressed pairs of diverse human genes. Typically, half of ≈50 observed regulators bind to both genes reproducibly, twice more than in independently expressed gene pairs. We also examine the largest set of co-expressed genes, which code for cytoplasmic ribosomal proteins. Numerous regulatory complexes are highly significant enriched in ribosomal genes compared to highly expressed non-ribosomal genes. We could not find any DNAassociated, strict sense master regulator. Despite major fluctuations in transcription factor binding, our machine learning model accurately predicted transcript levels using binding sites of 20+ regulators. Our pluralistic and stochastic theory is consistent with partially random binding patterns, redundancy, stochastic regulator binding, burst-like expression, degeneracy of binding motifs and massive regulatory rewiring during evolution.

Original languageEnglish (US)
Pages (from-to)4595-4609
Number of pages15
JournalNucleic acids research
Volume44
Issue number10
DOIs
StatePublished - Jun 2 2016

ASJC Scopus subject areas

  • Genetics

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    Salas, E. N., Shu, J., Cserhati, M. F., Weeks, D. P., & Ladunga, I. (2016). Pluralistic and stochastic gene regulation: Examples, models and consistent theory. Nucleic acids research, 44(10), 4595-4609. https://doi.org/10.1093/nar/gkw042