A novel Boolean network inference strategy to model early hematopoiesis aging.

Autor:	Hérault L; Aix Marseille Université, CNRS, Marseille I2M, France.; Epigenetic Factors in Normal and Malignant Hematopoiesis Team, Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France., Poplineau M; Epigenetic Factors in Normal and Malignant Hematopoiesis Team, Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France., Duprez E; Epigenetic Factors in Normal and Malignant Hematopoiesis Team, Aix Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France., Remy É; Aix Marseille Université, CNRS, Marseille I2M, France.
Jazyk:	angličtina
Zdroj:	Computational and structural biotechnology journal [Comput Struct Biotechnol J] 2022 Nov 02; Vol. 21, pp. 21-33. Date of Electronic Publication: 2022 Nov 02 (Print Publication: 2023).
DOI:	10.1016/j.csbj.2022.10.040
Abstrakt:	Hematopoietic stem cell (HSC) aging is a multifactorial event leading to changes in HSC properties and functions, which are intrinsically coordinated and affect the early hematopoiesis. To better understand the mechanisms and factors controlling these changes, we developed an original strategy to construct a Boolean model of HSC differentiation. Based on our previous scRNA-seq data, we exhaustively characterized active transcription modules or regulons along the differentiation trajectory and constructed an influence graph between 15 selected components involved in the dynamics of the process. Then we defined dynamical constraints between observed cellular states along the trajectory and using answer set programming with in silico perturbation analysis, we obtained a Boolean model explaining the early priming of HSCs. Finally, perturbations of the model based on age-related changes revealed important deregulations, such as the overactivation of Egr1 and Junb or the loss of Cebpa activation by Gata2. These new regulatory mechanisms were found to be relevant for the myeloid bias of aged HSC and explain the decreased transcriptional priming of HSCs to all mature cell types except megakaryocytes. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2022 The Authors.)
Databáze:	MEDLINE
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