Biology subjects

Barnada, S. M.

Publications and source records attributed to Barnada, S. M..

3 recordsLinked to original sources

bioRxiv2023

Non-redundant roles for the human mRNA decapping cofactor paralogs DCP1a and DCP1b

Eukaryotic gene expression is regulated at both the transcriptional and post-transcriptional levels, with disruption of regulation contributing significantly to human diseases. In particular, the 5 m7G mRNA cap is the central node in post-transcriptional regulation, participating in both mRNA stabilization and translation efficiency. DCP1a and DCP1b are paralogous cofactor proteins of the major mRNA cap hydrolase DCP2. As lower eukaryotes have a single DCP1 cofactor, the functional advantages gained by this evolutionary divergence remain unclear. Here we report the first functional dissection of DCP1a and DCP1b, demonstrating that DCP1a and DCP1b are distinct, non-redundant cofactors of the decapping enzyme DCP2, with unique roles in decapping complex integrity and specificity. Specifically, DCP1a is essential for decapping complex assembly and for interactions between the decapping complex and mRNA cap binding proteins. In contrast, DCP1b is essential for decapping complex interactions with the translational machinery. Additionally, DCP1a and DCP1b impact the turnover of distinct mRNAs. The observation that different ontological groups of mRNA molecules are regulated by DCP1a and DCP1b, along with their non-redundant roles in decapping complex integrity, provides the first evidence that these highly similar paralogs have qualitatively distinct functions. Furthermore, these observations implicate both DCP1a and DCP1b in transcript buffering.

biochemistry↗

bioRxiv2022

JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer disease

Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimers disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that upregulation of the AP-1 subunit c-JUN triggers decondensation of genomic regions containing TEs. This leads to cytoplasmic accumulation of TE-derived RNA-DNA hybrids, activation of the cGAS-STING cascade, and increased cleaved caspase-3 levels, suggesting initiation of programmed cell death in progenitor cells and neurons. Notably, inhibiting c-JUN effectively blocks all the downstream molecular processes and rescues neuronal death and impaired neurogenesis in the AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages.

genomics↗

bioRxiv2022

Genomic features underlie the co-option of SVA transposons as cis-regulatory elements in human pluripotent stem cells

Domestication of transposable elements (TEs) into functional cis-regulatory elements is a widespread phenomenon. However, the mechanisms behind why some TEs are co-opted as functional enhancers while others are not are underappreciated. SINE-VNTR-Alus (SVAs) are the youngest group of transposons in the human genome, where [~]3,700 copies are annotated, nearly half of which are human-specific. Many studies indicate that SVAs are among the most frequently co-opted TEs in human gene regulation, but the mechanisms underlying such processes have not yet been thoroughly investigated. Here, we leveraged CRISPR-interference (CRISPRi), computational and functional genomics to elucidate the genomic features that underlie SVA domestication into human stem-cell gene regulation. We found that [~]750 SVAs are co-opted as functional cis-regulatory elements in human induced pluripotent stem cells. These SVAs are significantly closer to genes and harbor more transcription factor binding sites than non-co-opted SVAs. We show that a long DNA motif composed of flanking YY1/2 and OCT4 binding sites is enriched in the co-opted SVAs and that these two transcription factors bind consecutively on the TE sequence. We used CRISPRi to epigenetically repress active SVAs in stem cell-like NCCIT cells. Epigenetic perturbation of active SVAs strongly attenuated YY1/OCT4 binding and influenced neighboring gene expression. Ultimately, SVA repression resulted in [~]3,000 differentially expressed genes, 131 of which were the nearest gene to an annotated SVA. In summary, we demonstrated that SVAs modulate human gene expression, and uncovered that location and sequence composition contribute to SVA domestication into gene regulatory networks.

genomics↗