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Longitudinal blood transcriptome analysis of two patients with cyclic thrombocytopenia

ABSTRACT: Cyclic thrombocytopenia (CTP) is a rare disease of characterized by periodic platelet count oscillations of uncertain etiology. As part of a study that applied systems biology approaches to investigate two patients with CTP, we performed whole blood transcriptome analyses on semi-weekly collected sequential samples covering two platelet cycles. This blood transcriptome analysis revealed cyclical gene expression changes of platelet-specific genes that are in parallel with, and leading platelet count oscillations in both patients. In addition, erythrocyte-specific genes and neutrophil-specific genes also exhibited cyclic patterns which preceded platelet-specific genes. These findings revealed cyclical trilineage hematopoiesis, most pronounced in megakaryopoiesis in both patients with CTP.

ORGANISM(S): Homo sapiens

PROVIDER: GSE179076 | GEO | 2022/04/05

REPOSITORIES: GEO

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Project description:Oscillatory phenomena are ubiquitous across different biological scales, from individual cells to tissues and whole organisms. In physical systems, oscillatory behaviour can emerge from weak coupling of independent stochastic elements. Once established, oscillations can drive coordinated group behaviour and encode robust information through oscillation frequency or amplitude. Here we use experimentation and modelling to understand the emergence and information coding properties of oscillatory cyclic adenosine monophosphate (cAMP) signaling in D. discoideum. Oscillatory cAMP signaling drives aggregation of individual amoebae and coordinated temporal shifts in gene expression. However, it is unknown how the collective behaviour emerges and attenuates in an auto-regulatory manner where temporal transcriptional regulation must decode variation in cAMP pulse count, frequency, or amplitude. To address these questions, we identified a transcription factor, Hbx5, that is essential for the initiation of collective behaviour and its activity provides a single-cell readout of the earliest sign of cAMP signaling. This reveals stochastic pulses in cAMP signaling precede collective oscillations, with Hbx5 dependent transcriptional feedback enhancing signal sensitivity necessary for the emergence of collective oscillations. We demonstrate that once collective oscillations have been established, another cAMP-regulated transcription factor, GtaC, required for subsequent developmental progression becomes activated. Modelling and experimentation suggest that temporal differences in transcription factor activation arise from differences in the threshold at which the protein kinase, ErkB, influences their activity. This leads us to propose that changes in the amplitude of cAMP oscillations during development encode temporal information, driving the orderly progression of development. These studies thus provide crucial insights into the principles driving collective behaviour and the evolution of multicellular systems.

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Longitudinal blood transcriptome analysis of two patients with cyclic thrombocytopenia

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