Research output

Transposable elements (TEs) comprise nearly half of mammalian genomes and have shaped genome architecture, chromatin organization, and transcriptional landscapes. Thanks to recent advances in long-read sequencing and functional (epi)genomics, the focus has shifted from TE families to individual TE loci, revealing widespread, locus-specific regulatory roles. While most TEs have lost the capacity to mobilize, they still retain a DNA form and, when transcribed, an RNA form, both of which can affect genome regulation. TEs can serve as alternative promoters, exons, splicing regulators, and 3' end modulators. They can also act as enhancers, drive three-dimensional (3D) genome organization, and give rise to long non-coding RNAs (lncRNAs) that serve as platforms for transcriptional and chromatin regulators. Mechanistically, TE repression involves DNA methylation, histone modification, phase-separated condensates, RNA modifications, RNA degradation, and nuclear compartmentalization, yet this repression can be selectively lifted during development or stress to expand regulatory potential. TEs therefore contribute to cell-type identity, developmental transitions, and responses to environmental stimuli, while their dysregulation is linked to human disorders including neurodegeneration, cancer, and autoimmune disease. TEs also hold translational promise as biomarkers and tools for gene and cell engineering. In summary, the pervasive integration of TEs as mini-genes, structural scaffolds, and regulatory elements redefines our view of the genome: rather than a gene-centric landscape dotted with repetitive "junk," mammalian DNA is a TE-rich ecosystem in which TEs drive gene regulatory networks and evolution.

Transposable elements (TEs) in the human genome are the heritage of ancient parasitic infections. While most of human DNA comprises TEs and TE-derived elements, their repetitive nature poses technical challenges; thus, little is known about their positional identity and regulatory roles. Here, by integrating long-read and multidimensional transcriptional analyses, we investigate when, where and how TEs become part of a gene. We characterize how TE-derived isoforms change across mouse-human variation and how they are linked to gene regulatory networks controlling cell states during differentiation, organogenesis and health (aging and pathological states). Mechanistically, we identify an RNA degradation-dependent and splicing-dependent quality control mechanism that operates independently of conventional mechanisms of TE suppression, such as DNA methylation and heterochromatinization, and prevents TE-chimera expression and TE-induced cell differentiation. Overall, our findings unveil mechanisms by which viral-derived elements enhance transcriptome plasticity.

N,2'-O-dimethyladenosine (mAm) is an abundant mRNA modification that impacts multiple diseases, but its function remains controversial because the mAm reader is unknown. Using quantitative proteomics, we identified transcriptional terminator premature cleavage factor II (PCF11) as a mAm-specific reader in human cells. Direct quantification of mature versus nascent RNAs reveals that mAm does not regulate mRNA stability but promotes nascent transcription. Mechanistically, mAm functions by sequestering PCF11 away from proximal RNA polymerase II (RNA Pol II). This suppresses PCF11 from dissociating RNA Pol II near transcription start sites, thereby promoting full-length transcription of mAm-modified RNAs. mAm's unique relationship with PCF11 means mAm function is enhanced when PCF11 is reduced, which occurs during all-trans-retinoic-acid (ATRA)-induced neuroblastoma-differentiation therapy. Here, mAm promotes expression of ATF3, which represses neuroblastoma biomarker MYCN. Depleting mAm suppresses MYCN repression in ATRA-treated neuroblastoma and maintains their tumor-stem-like properties. Collectively, we characterize mAm as an anti-terminator RNA modification that suppresses premature termination and modulates neuroblastoma's therapeutic response.

Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.

Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is an emerging drug discovery platform. PROTAC molecules, which typically contain a target protein ligand linked to an E3 ligase ligand, recruit a target protein to the E3 ligase to induce its ubiquitination and degradation. Here, we applied PROTAC approaches to develop broad-spectrum antivirals targeting key host factors for many viruses and virus-specific antivirals targeting unique viral proteins. For host-directed antivirals, we identified a small-molecule degrader, FM-74-103, that elicits selective degradation of human GSPT1, a translation termination factor. FM-74-103-mediated GSPT1 degradation inhibits both RNA and DNA viruses. Among virus-specific antivirals, we developed viral RNA oligonucleotide-based bifunctional molecules (Destroyers). As a proof of principle, RNA mimics of viral promoter sequences were used as heterobifunctional molecules to recruit and target influenza viral polymerase for degradation. This work highlights the broad utility of TPD to rationally design and develop next-generation antivirals.