2026-04-29T04:08:34Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/189752024-11-30T00:37:54Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Martínez-Balsalobre, Elena
author
García-Castillo, Jesús
author
García-Moreno, Diana
author
Naranjo-Sánchez, Elena
author
Fernández-Lajarín, Miriam
author
Blasco, MA
author
Alcaraz-Pérez, Francisca
author
Mulero, Victoriano
author
Cayuela, María L
funder
Ministerio de Ciencia e Innovación (España)
funder
Fundación Ramón Areces
funder
University of Murcia (España)
2024-03-18T10:36:56Z
2024-03-18T10:36:56Z
2023-09-22
Nat Commun . 2023 ;14(1):5912.
http://hdl.handle.net/20.500.12105/18975
37737237
10.1038/s41467-023-41472-7
2041-1723
Nature communications
Telomerase RNA (TERC) has a noncanonical function in myelopoiesis binding to a consensus DNA binding sequence and attracting RNA polymerase II (RNA Pol II), thus facilitating myeloid gene expression. The CR4/CR5 domain of TERC is known to play this role, since a mutation of this domain found in dyskeratosis congenita (DC) patients decreases its affinity for RNA Pol II, impairing its myelopoietic activity as a result. In this study, we report that two aptamers, short single-stranded oligonucleotides, based on the CR4/CR5 domain were able to increase myelopoiesis without affecting erythropoiesis in zebrafish. Mechanistically, the aptamers functioned as full terc; that is, they increased the expression of master myeloid genes, independently of endogenous terc, by interacting with RNA Pol II and with the terc-binding sequences of the regulatory regions of such genes, enforcing their transcription. Importantly, aptamers harboring the CR4/CR5 mutation that was found in DC patients failed to perform all these functions. The therapeutic potential of the aptamers for treating neutropenia was demonstrated in several preclinical models. The findings of this study have identified two potential therapeutic agents for DC and other neutropenic patients.
eng
Telomerase RNA-based aptamers restore defective myelopoiesis in congenital neutropenic syndromes.
journal article
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