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Kreibich, Elisa; Krebs, Arnaud R.
doi: 10.1002/1873-3468.14686pmid: 37343149
DNA methylation (5mC) is an essential epigenetic mark associated with transcriptional silencing. The role of 5mC in transcriptional repression is well established for a few hundred genes through methylation of their promoters. Yet, whether 5mC contributes more broadly to gene expression is an important open question. 5mC removal has recently been associated with the activation of enhancers, opening the possibility that 5mC may globally contribute to the expression of genes defining cell identities. Here, we will review the evidence and molecular mechanisms that link 5mC with the activity of enhancers. We will discuss the spread and amplitude of the potential gene expression changes controlled by 5mC at enhancers, and how these may contribute to the determination of cell identities during development.
Reiss, Matthew; Keegan, Joshua; Aldrich, Anne; Lyons, Shawn M.; Flynn, Rachel Litman
doi: 10.1002/1873-3468.14639pmid: 37191774
The telomeric repeat‐containing RNA, TERRA, associates with both telomeric DNA and telomeric proteins, often forming RNA:DNA hybrids (R‐loops). TERRA is most abundant in cancer cells utilizing the alternative lengthening of telomeres (ALT) pathway for telomere maintenance, suggesting that persistent TERRA R‐loops may contribute to activation of the ALT mechanism. Therefore, we sought to identify the enzyme(s) that regulate TERRA metabolism in mammalian cells. Here, we identify that the 5′–3′ exoribonuclease XRN2 regulates the stability of TERRA RNA. Moreover, while stabilization of TERRA alone was insufficient to drive ALT, depletion of XRN2 in ALT‐positive cells led to a significant increase in TERRA R‐loops and exacerbated ALT activity. Together, our findings highlight XRN2 as a key determinant of TERRA metabolism and telomere stability in cancer cells that rely on the ALT pathway.
Karasawa, Takumi; Saito, Namiho; Koshikawa, Shigeyuki
doi: 10.1002/1873-3468.14637pmid: 37194970
The co‐option of regulatory genes has the potential to play an important role in the evolutionary gain of new traits. However, the changes at the sequence level that underlie such a co‐option event are still elusive. We identified the changes in the cis‐regulatory sequence of wingless that caused co‐option of wingless and led to its expression in new places in Drosophila guttifera, which has unique pigmentation patterns on its wings. The newly gained function of gene expression activation was acquired evolutionarily via a combination of pre‐existing sequences containing a putative binding site for SMAD transcription factors that exhibit an ancestral function in driving expression at crossveins, and a sequence that is specific to the lineage leading to D. guttifera.
Kara, Evan; McCambridge, Aidan; Proffer, Megan; Dilts, Carol; Pumnea, Brooke; Eshak, John; Smith, Korey A.; Fielder, Isaac; Doyle, Dominique A.; Ortega, Bianca M.; Mukatash, Yousif; Malik, Noor; Mohammed, Ammaar R.; Govani, Deep; Niepielko, Matthew G.; Gao, Ming
Li, Yingxiang; Liu, Chengdong; Bai, Xuanxuan; Li, Mingyu; Duan, Cunming
doi: 10.1002/1873-3468.14670pmid: 37259581
Using a zebrafish ionocyte model, transcriptomics and genetic analyses were performed to identify pathways and genes involved in cell quiescence‐proliferation regulation. Gene ontology and Kyoto encyclopedia of genes and genomes pathway analyses revealed that genes involved in transcription regulation, cell cycle, Foxo signalling and Wnt signalling pathway are enriched among the up‐regulated genes while those involved in ion transport, cell adhesion and oxidation–reduction are enriched among the down‐regulated genes. Among the top up‐regulated genes is FK506‐binding protein 5 (Fkbp5). Genetic deletion and pharmacological inhibition of Fkbp5 abolished ionocyte reactivation and impaired Akt signalling. Forced expression of a constitutively active form of Akt rescued the defects caused by Fkbp5 inhibition. These results uncover a key role of Fbkp5 in regulating the quiescence‐proliferation decision via Akt signalling.
Grooms, Noa W.F.; Fitzgerald, Michael Q.; Zuckerman, Binyamin; Ureña, Samuel E.; Weinberger, Leor S.; Chung, Samuel H.
doi: 10.1002/1873-3468.14684pmid: 37300530
A conditioning lesion of the peripheral sensory axon triggers robust central axon regeneration in mammals. We trigger conditioned regeneration in the Caenorhabditis elegans ASJ neuron by laser surgery or genetic disruption of sensory pathways. Conditioning upregulates thioredoxin‐1 (trx‐1) expression, as indicated by trx‐1 promoter‐driven expression of green fluorescent protein and fluorescence in situ hybridization (FISH), suggesting trx‐1 levels and associated fluorescence indicate regenerative capacity. The redox activity of trx‐1 functionally enhances conditioned regeneration, but both redox‐dependent and ‐independent activity inhibit non‐conditioned regeneration. Six strains isolated in a forward genetic screen for reduced fluorescence, which suggests diminished regenerative potential, also show reduced axon outgrowth. We demonstrate an association between trx‐1 expression and the conditioned state that we leverage to rapidly assess regenerative capacity.
Villalobos, Pablo; Carvajal, Alonso I.; Castro‐Fernández, Víctor; Babul, Jorge; Ramírez‐Sarmiento, César A.; Medina, Exequiel
doi: 10.1002/1873-3468.14665pmid: 37199668
Human FoxP proteins share a highly conserved DNA‐binding domain that dimerizes via three‐dimensional domain swapping, although showing varying oligomerization propensities among its members. Here, we present an experimental and computational characterization of all human FoxP proteins to unravel how their amino acid substitutions impact their folding and dimerization mechanism. We solved the crystal structure of the forkhead domain of FoxP4 to then perform a comparison across all members, finding that their sequence changes impact not only the structural heterogeneity of their forkhead domains but also the protein–protein association energy barrier. Lastly, we demonstrate that the accumulation of a monomeric intermediate is an oligomerization‐dependent feature rather than a common aspect of monomers and dimers in this protein subfamily.
doi: 10.1002/1873-3468.14681pmid: 37316461
MicroRNAs are among the key modulators of placental transcriptome dynamics. This study aimed at comparative profiling of urinary (sampling at 228–230 gestational days, g.days), serum (217–230 g.days), and placental (279–286 g.days) microRNAs in three healthy pregnant women using miRNome sequencing. Placenta showed significant enrichment of microRNAs compared with serum and urine (1174, 341, and 193, respectively; P < 10−5). All sample types shared 153 microRNAs, representing candidate biomarkers for placental health. Urine samples contained eight of 56 transcripts from the placenta‐specific chromosome 19 microRNA cluster C19MC and one of 91 transcripts (miR‐432‐5p) from the chromosome 14 cluster C14MC. These data suggest an active filtering at the maternal–fetal interface in passing through only selected microRNAs. Urine represents a valid source to monitor the signature of placenta‐expressed microRNAs that are differentially expressed in pregnancy complications.
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Me31B/DDX6 is a DEAD‐box family RNA helicase playing roles in post‐transcriptional RNA regulation in different cell types and species. Despite the known motifs/domains of Me31B, the in vivo functions of the motifs remain unclear. Here, we used the Drosophila germline as a model and used CRISPR to mutate the key Me31B motifs/domains: helicase domain, N‐terminal domain, C‐terminal domain and FDF‐binding motif. Then, we performed screening characterization on the mutants and report the effects of the mutations on the Drosophila germline, on processes such as fertility, oogenesis, embryo patterning, germline mRNA regulation and Me31B protein expression. The study indicates that the Me31B motifs contribute different functions to the protein and are needed for proper germline development, providing insights into the in vivo working mechanism of the helicase.