PUBLICATION

Telomerase RNA recruits RNA polymerase II to target gene promoters to enhance myelopoiesis

Authors
García-Castillo, J., Alcaraz-Pérez, F., Martínez-Balsalobre, E., García-Moreno, D., Rossmann, M.P., Fernández-Lajarín, M., Bernabé-García, M., Pérez-Oliva, A.B., Rodríguez-Cortez, V.C., Bueno, C., Adatto, I., Agarwal, S., Menéndez, P., Zon, L.I., Mulero, V., Cayuela, M.L.
ID
ZDB-PUB-210807-2
Date
2021
Source
Proceedings of the National Academy of Sciences of the United States of America   118(32): (Journal)
Registered Authors
Adatto, Isaac, Zon, Leonard I.
Keywords
dyskeratosis congenita, myelopoiesis, telomerase RNA component, zebrafish
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Binding Sites
  • Cells, Cultured
  • Dyskeratosis Congenita/genetics*
  • Dyskeratosis Congenita/pathology
  • Gene Expression Regulation
  • Humans
  • Induced Pluripotent Stem Cells/pathology
  • Larva/genetics
  • Mutation
  • Myelopoiesis/genetics
  • Myelopoiesis/physiology*
  • Promoter Regions, Genetic
  • Protein Domains
  • RNA/genetics
  • RNA/metabolism*
  • RNA Polymerase II/genetics*
  • RNA Polymerase II/metabolism
  • Telomerase/genetics
  • Telomerase/metabolism*
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
PubMed
34353901 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Dyskeratosis congenita (DC) is a rare inherited bone marrow failure and cancer predisposition syndrome caused by mutations in telomerase or telomeric proteins. Here, we report that zebrafish telomerase RNA (terc) binds to specific DNA sequences of master myeloid genes and controls their expression by recruiting RNA Polymerase II (Pol II). Zebrafish terc harboring the CR4-CR5 domain mutation found in DC patients hardly interacted with Pol II and failed to regulate myeloid gene expression in vivo and to increase their transcription rates in vitro. Similarly, TERC regulated myeloid gene expression and Pol II promoter occupancy in human myeloid progenitor cells. Strikingly, induced pluripotent stem cells derived from DC patients with a TERC mutation in the CR4-CR5 domain showed impaired myelopoiesis, while those with mutated telomerase catalytic subunit differentiated normally. Our findings show that TERC acts as a transcription factor, revealing a target for therapeutic intervention in DC patients.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping