Biology subjects

Tristan-Ramos, P.

Publications and source records attributed to Tristan-Ramos, P..

4 recordsLinked to original sources

bioRxiv2025

Control of retrotransposon-driven activation of the interferon response by the double-stranded RNA binding protein DGCR8

The type I interferon (IFN) response is the main innate immune pathway against viruses in mammals. This pathway must be tightly regulated to prevent viral spread while avoiding excessive immune responses. Here, we show that inactivation of the double-stranded RNA (dsRNA)-binding protein DGCR8 unleashes the IFN response in human cells. We demonstrate that DGCR8 restricts the accumulation of endogenous dsRNA originating from protein-coding mRNAs that harbour transposable elements (TEs), primarily Alu. We propose that DGCR8 binding to TE-rich mRNAs is essential to resolve dsRNA structures, and in its absence, accumulated dsRNA signals through the RIG-I-like signalling pathway triggering the IFN response. This mechanism is relevant to conditions where DGCR8 expression levels are altered, including the 22q11.2 deletion syndrome (22qDS). Supporting this, we show that 22qDS-derived cells exhibit an exacerbated type I IFN response which inversely correlated with DGCR8 levels. All these together demonstrate the importance of suppressing endogenous TE-dsRNA accumulation to prevent unwanted immune activation and associated disease pathogenesis.

molecular biology↗

bioRxiv2024

BMAL1 represses transposable elements independently of CLOCK in pluripotent cells

Circadian oscillations of gene transcripts rely on a negative feedback loop executed by the activating BMAL1-CLOCK heterodimer and its negative regulators PER and CRY. Although circadian rhythms and CLOCK protein are mostly absent during embryogenesis, the lack of BMAL1 during prenatal development causes an early aging phenotype during adulthood, suggesting that BMAL1 carries out an unknown non-circadian function during organism development that is fundamental for healthy adult life. Here, we show that BMAL1 interacts with TRIM28 and represses transcription of totipotency-associated MERVL retrotransposons in mouse pluripotent cells. Deletion of Bmal1 leads to genome-wide upregulation of MERVLs, changes in the three-dimensional organization of the genome, and acquisition of totipotency-associated features. Overall, we demonstrate that in pluripotent cells BMAL1 is redeployed as a transcriptional repressor of transposable elements (TEs) in a CLOCK-independent way. We propose that BMAL1-TRIM28 activity during prenatal life is essential for optimal health and life span in mammals.

molecular biology↗

bioRxiv2024

DGCR8 haploinsufficiency leads to primate-specific RNA dysregulation and pluripotency defects

The 22q11.2 deletion syndrome (22qDS) is caused by a microdeletion in chromosome 22, including DGCR8, an essential gene for miRNA production. The contribution of human DGCR8 hemizygosity to the disease is still unclear. In this study, we generated two human pluripotent cell models containing a single functional DGCR8 allele to elucidate its role on 22qDS. DGCR8+/-cells show increased apoptosis as well as self-renewal and differentiation defects in both the naive and primed states. The expression of primate-specific miRNAs was largely affected, due to impaired miRNA processing and chromatin accessibility. DGCR8+/- cells also displayed a pronounced reduction in human endogenous retrovirus class H (HERVH) expression, a primate-specific retroelement essential for pluripotency maintenance. Importantly, the reintroduction of primate-specific miRNAs as well as the miR-371-3 cluster rescued the cellular and molecular phenotypes of DGCR8+/-cells. Our results suggest that DGCR8 is haploinsufficient in humans and that miRNAs and transposable elements may have co-evolved in primates as part of an essential regulatory network to maintain stem cell identity.

molecular biology↗

bioRxiv2020

The tumor suppressor microRNA let-7 inhibits human LINE-1 retrotransposition

Nearly half of the human genome is made of transposable elements (TEs) whose activity continues to impact its structure and function. Among them, Long INterspersed Element class 1 (LINE-1 or L1) elements are the only autonomously active TEs in humans. L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect malignancy. Tumor suppressor microRNAs are [~]22nt RNAs that post-transcriptionally regulate oncogene expression and are frequently downregulated in cancer. Here we explore whether they also influence L1 mobilization. We found that downregulation of let-7 correlates with accumulation of L1 insertions in human lung cancer. Furthermore, we demonstrate that let-7 binds to the L1 mRNA and impairs the translation of the second L1-encoded protein, ORF2p, reducing its mobilization. Overall, our data uncover a new role for let-7, one of the most relevant microRNAs, which is to maintain somatic genome integrity by restricting L1 retrotransposition.

molecular biology↗