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

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.

Genomic, epigenomic, and transcriptomic signatures for telomerase complex components: a pan‐cancer analysis

“…For example, TERT serves as a transcriptional cofactor to regulate expression of a panel of oncogenic factors, and promotes cancer aggressiveness, resistance to oxidative stress, and anticancer drugs, and survival or proliferation [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]. TERC is associated with not only telomeres but also acts as a transcription factor to regulate the transcription of WNT, inflammation‐related, and myeloid genes [ 62 , 63 , 64 ]. In addition, the DKC1/NOP10/NHP2 complex‐mediated pseudouridylation broadly regulates RNA metabolism, including RNA stability, ribosome biogenesis, and splicing events [ 20 , 65 ].…”

Canonical and extra‐telomeric functions of telomerase: Implications for healthy ageing conferred by endurance training

“…TERC may act in concert with transcription factors. For instance, short hairpin RNA (shRNA) knockdown of TERC downregulated genes involved in myelopoiesis (CSF2, CSF3, SPI1) in human HL60 and U937 cells (neutrophil and monocyte progenitors) that relied on the recruitment of RNA polymerase II (García‐Castillo et al, 2021 ). Additionally, TERC is imported into the mitochondria, truncated to a shorter version (TERC‐53) and shuttled back into the cytosol where it regulates gene expression and cellular senescence independent of telomerase activity and telomere length (Zheng et al, 2019 ).…”

Zebrafish: a convenient tool for myelopoiesis research

“…Telomerase RNA (terc) is able to bind specific DNA sequences, recruits RNA polymerase II, and regulates the expression of myeloid genes (García-Castillo et al 2021 ). This function of terc is discovered using a zebrafish terc mutant with the CR4-CR5 domain mutation found in patients with dyskeratosis congenita (DC) in vivo and independent on the telomerase catalytic subunit.…”