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, Mulero, Victor, Zon, Leonard I.

Keywords

dyskeratosis congenita, myelopoiesis, telomerase RNA component, zebrafish

MeSH Terms

Mutation
Zebrafish/genetics
Induced Pluripotent Stem Cells/pathology
Animals, Genetically Modified
Gene Expression Regulation
Myelopoiesis/genetics
Myelopoiesis/physiology*
Larva/genetics
Promoter Regions, Genetic
Cells, Cultured
Animals
Humans
RNA/genetics
RNA/metabolism*
Protein Domains
Zebrafish Proteins/genetics
RNA Polymerase II/genetics*
RNA Polymerase II/metabolism
Binding Sites
Telomerase/genetics
Telomerase/metabolism*
Dyskeratosis Congenita/genetics*
Dyskeratosis Congenita/pathology

(all 23)

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

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
csf3a	AB + MO2-linc-tr	standard conditions	Long-pec	caudal hematopoietic tissue	RTPCR	Fig. S1
csf3a	linc-tr^{zf3578/zf3578}	standard conditions	Long-pec	caudal hematopoietic tissue	RTPCR	Fig. 1
csf3a	zf3577Tg/zf3577Tg	standard conditions	Long-pec	caudal hematopoietic tissue	RTPCR	Fig. 1
csf3b	AB + MO2-linc-tr	standard conditions	Long-pec	caudal hematopoietic tissue	RTPCR	Fig. S1
csf3b	linc-tr^{zf3578/zf3578}	standard conditions	Long-pec	caudal hematopoietic tissue	RTPCR	Fig. 1
csf3b	zf3577Tg/zf3577Tg	standard conditions	Long-pec	caudal hematopoietic tissue	RTPCR	Fig. 1
EGFP	i114Tg/i114Tg; zf3577Tg/zf3577Tg	standard conditions	Protruding-mouth	caudal hematopoietic tissue neutrophil	IFL	Fig. 1
EGFP	linc-tr^{zf3578/zf3578}; i114Tg/i114Tg	standard conditions	Protruding-mouth	caudal hematopoietic tissue neutrophil	IFL	Fig. 1
spi1a	AB + MO2-linc-tr	standard conditions	Long-pec	caudal hematopoietic tissue	RTPCR	Fig. S1
spi1b	AB + MO2-linc-tr	standard conditions	Long-pec	caudal hematopoietic tissue	RTPCR	Fig. S1

1 - 10 of 15

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB + MO2-linc-tr	standard conditions	Long-pec	caudal hematopoietic tissue csf3a expression decreased amount, abnormal	Fig. S1
AB + MO2-linc-tr	standard conditions	Long-pec	caudal hematopoietic tissue csf3b expression decreased amount, abnormal	Fig. S1
AB + MO2-linc-tr	standard conditions	Long-pec	caudal hematopoietic tissue spi1a expression decreased amount, abnormal	Fig. S1
AB + MO2-linc-tr	standard conditions	Long-pec	caudal hematopoietic tissue spi1b expression decreased amount, abnormal	Fig. S1
AB + MO2-linc-tr	standard conditions	Long-pec	caudal hematopoietic tissue terc expression decreased amount, abnormal	Fig. S1
i114Tg/i114Tg; zf3577Tg/zf3577Tg	standard conditions	Protruding-mouth	caudal hematopoietic tissue neutrophil EGFP expression increased amount, abnormal	Fig. 1
linc-tr^{zf3578/zf3578}	standard conditions	Long-pec	caudal hematopoietic tissue csf3a expression decreased amount, abnormal	Fig. 1
linc-tr^{zf3578/zf3578}	standard conditions	Long-pec	caudal hematopoietic tissue csf3b expression decreased amount, abnormal	Fig. 1
linc-tr^{zf3578/zf3578}	standard conditions	Long-pec	caudal hematopoietic tissue spi1b expression decreased amount, abnormal	Fig. 1
linc-tr^{zf3578/zf3578}	standard conditions	Long-pec	caudal hematopoietic tissue terc expression decreased amount, abnormal	Fig. 1

1 - 10 of 15

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
i114Tg	Tg(mpx:GFP)	Transgenic Insertion
zf3577Tg	Tg(drl:linc-tr,myl7:EGFP)	Transgenic Insertion
zf3578		Small Deletion	linc-tr

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
dyskeratosis congenita	linc-tr^{zf3578/zf3578}	standard conditions	TAS
dyskeratosis congenita	zf3577Tg/zf3577Tg	standard conditions	TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
gata1a	MO2-gata1a	MRPHLNO
linc-tr	MO1-linc-tr	MRPHLNO
linc-tr	MO2-linc-tr	MRPHLNO
linc-tr	MO3-linc-tr	MRPHLNO

Fish

Fish
AB + MO2-linc-tr
i114Tg/i114Tg; zf3577Tg/zf3577Tg
linc-tr^{zf3578/zf3578}
linc-tr^{zf3578/zf3578}; i114Tg/i114Tg
zf3577Tg/zf3577Tg

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GFP	EFG	GFP

Mapping

García-Castillo et al., 2021 ZDB-PUB-210807-2 PMID:34353901

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

García-Castillo et al., 2021

ZDB-PUB-210807-2
PMID:34353901